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Systematic Review: Benets and Harms of In-Hospital Use ofRecombinant Factor VIIa for Off-Label IndicationsVeronica Yank, MD; C. Vaughan Tuohy, BS; Aaron C. Logan, MD, PhD; Dena M. Bravata, MD, MS; Kristan Staudenmayer, MD, MS;Robin Eisenhut, BA; Vandana Sundaram, MPH; Donal McMahon, MSc, PhD; Ingram Olkin, PhD; Kathryn M. McDonald, MM;Douglas K. Owens, MD, MS; and Randall S. Stafford, MD, PhD

Background: Recombinant factor VIIa (rFVIIa), a hemostatic agentapproved for hemophilia, is increasingly used for off-label indications.

Purpose: To evaluate the benefits and harms of rFVIIa use for 5off-label, in-hospital indications: intracranial hemorrhage, cardiacsurgery, trauma, liver transplantation, and prostatectomy.

Data Sources: Ten databases (including PubMed, EMBASE, and theCochrane Library) queried from inception through December 2010.Articles published in English were analyzed.

Study Selection: Two reviewers independently screened titles andabstracts to identify clinical use of rFVIIa for the selected indicationsand identified all randomized, controlled trials (RCTs) and observa-

tional studies for full-text review.Data Extraction: Two reviewers independently assessed study char-acteristics and rated study quality and indication-wide strength ofevidence.

Data Synthesis: 16 RCTs, 26 comparative observational studies,and 22 noncomparative observational studies met inclusion criteria.Identified comparators were limited to placebo (RCTs) or usual care(observational studies). For intracranial hemorrhage, mortality was

not improved with rFVIIa use across a range of doses. Arterialthromboembolism was increased with medium-dose rFVIIa use (riskdifference [RD], 0.03 [95% CI, 0.01 to 0.06]) and high-dose rFVIIause (RD, 0.06 [CI, 0.01 to 0.11]). For adult cardiac surgery, therewas no mortality difference, but there was an increased risk for thromboembolism (RD, 0.05 [CI, 0.01 to 0.10]) with rFVIIa. For body trauma, there were no differences in mortality or thrombo-embolism, but there was a reduced risk for the acute respiratorydistress syndrome (RD, 0.05 [CI, 0.02 to 0.08]). Mortality washigher in observational studies than in RCTs.

Limitations: The amount and strength of evidence were low for most outcomes and indications. Publication bias could not beexcluded.

Conclusion: Limited available evidence for 5 off-label indicationssuggests no mortality reduction with rFVIIa use. For some indica-tions, it increases thromboembolism.

Primary Funding Source: Agency for Healthcare Research andQuality.

Ann Intern Med. 2011;154:529-540. www.annals.orgFor author affiliations, see end of text.

Recombinant factor VIIa (rFVIIa) is an expensive and

potent procoagulant. The U.S. Food and Drug Ad-ministration (FDA) approved intravenous use of rFVIIa in1999 for patients with hemophilia A or B and antibody in-hibitors against standard-factor replacements. Recently, its usehas expanded beyond these approved indications to encom-pass a wide range of in-hospital, off-label applications.

Off-label drug use refers to any application that devi-ates from FDA-approved use. The FDA drug-approvalprocess mandates that randomized, clinical trials demon-strate efcacy and safety. Once approval is given, however,physicians are free to use the drug for other indications. Although off-label use is legal and allows for rapid adop-

tion of some therapies, the available evidence supporting itusually falls short of the rigor that accompanies FDA re-view. Even though the resulting uncertainty may be accept-able, concerns increase when off-label use is applied toconditions that are clinically distinct from approved indi-cations or it is done frequently, is costly, or is associated with important side effects or harms.

The off-label use of rFVIIa for hospitalized patientshas increased, despite concerns about efcacy and safety,including evidence suggesting an increased rate of throm-boembolic events (15). Our comparative effectiveness re-view evaluates the benets and harms of in-hospital, off-label use of rFVIIa in adults for the selected indications of

intracranial hemorrhage (ICH), cardiac surgery, trauma,

liver transplantation, and prostatectomy.

METHODSThe Agency for Healthcare Research and Quality

(AHRQ) commissioned the full report, which is available,including the search strategies and detailed evidence tables,at the AHRQ Web site (6). We developed and followedstandardized protocols for data searches, extraction, quality assessments, and syntheses.

See also:

PrintEditorial comment. . . . . . . . . . . . . . . . . . . . . . . . . . 566Related article. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516

Web-OnlyAppendix TablesAppendix FigureCME quizConversion of graphics into slides

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Data Sources and SearchesSearches

In collaboration with a research librarian, we devel-oped individualized search strategies for 10 biblio-graphic databases from inception through 31 December2010: PubMed, EMBASE, the Cochrane Library,ACP

Journal Club, Database of Abstracts of Reviews of Ef-fects, Cochrane Central Register of Controlled Trials,CMR, Health Technology Assessment, National HealthService Economic Evaluation Database, and BIOSIS. We contacted experts and reviewed bibliographies of identied systematic reviews, les supplied by the man-ufacturer, and the manufacturers Web site. A librarianexpert on gray literature (sources other than publishedmaterials indexed in bibliographic databases) searchedregulatory sites, clinical trial registries, conference pro-ceedings, and grant-funded and federally funded re-search sites and contacted authors of abstracts to deter-

mine whether full reports had been subsequently published.

Inclusion Criteria We sought studies that compared the use of rFVIIa

with alternative therapies, placebo, or usual care for hospi-talized patients with 5 off-label indications: ICH, cardiacsurgery, trauma, liver transplantation, and prostatectomy.For inclusion, studies had to address direct or surrogateclinical outcomes. We did not contact authors about re-sults that were not reported in their publications. We ex-cluded studies published only as abstracts and studies of human factor VIIa or modied recombinant forms underdevelopment; studies on use of rFVIIa for on-label indica-tions and rFVIIa applied to patients substantially similar tothose for whom on-label indications are approved (for ex-ample, Glanzmann thrombasthenia); and studies whoseoutcome measures (for example, drug half-life) are not rel-evant to efcacy, effectiveness, or safety. Lastly, we re-viewed the English-language abstracts and references of studies published in non-English languages. Among these, we identied 2 small comparative studies likely eligible foreffectiveness review (randomized, controlled trial [RCT] of cardiac surgery [11 patients who received rFVIIa] [7] andcomparative cohort study of brain trauma [7 who receivedrFVIIa] [8]) and 6 case series reports (range, 16 to 35patients) (914) likely eligible for harms analyses if we hadthe capacity to do a full-text review. The RCT was usedfor sensitivity testing, with similar results to those re-ported here. The other articles not published in English were excluded from further review on the basis of a lack of capacity for translation and the determination thatsuch exclusions were unlikely to bias our ndings be-cause few articles were identied and the studies en-rolled few patients.

Study SelectionTwo reviewers independently screened titles and ab-

stracts to identify clinical use of rFVIIa for the selectedindications and identied all RCTs and observational stud-ies for full-text review. For the effectiveness analyses, weincluded RCTs and comparative observational studies. We

reviewed all RCTs in detail, whereas we reviewed onlycomparative observational studies of fair or good quality indetail. We used comparative observational studies of poorquality for qualitative sensitivity analyses. Patients fromoverlapping or duplicate articles reporting on the same pa-tient population were included only once.

Although noncomparative studies are a less reliablesource of evidence than comparative studies, they may re-port infrequent events not identied in RCTs (15). Givenconcerns about the possibility of clinically signicantharms, we included registries and cohorts with at least 15total patients in the harms analyses. We selected 15 pa-tients as the minimum threshold because the risk for bias(for example, selective reporting) is probably increased insmaller reports. We also included the treatment groups of all comparative studies in the harms analyses.

Data Extraction and Quality AssessmentTwo reviewers independently rated study quality and

indication-wide strength of evidence and abstracted study characteristics by using pretested electronic forms. Study quality and indication-wide strength of evidence were eval-uated by using well-established criteria (1625) and a pre-dened systematic approach described further in the AHRQ report (6). The quality criteria were specic to thestudy type and were used to assign each study a quality score from the ordinal scale of poor, fair, or good by usingqualitative determinations rather than numerical scores.For RCTs, essential quality elements included appropriaterandomization, allocation concealment, blinding, and ab-sence of differential follow-up. For observational studies,essential quality elements included appropriate methods togenerate comparability of groups and control for con-founding, appropriate blinding, and absence of differentialfollow-up. Studies that did not achieve (or did not ade-quately report) these elements were assigned a quality scoreof poor. Studies that achieved these partially or fully werefelt to have a lower risk for bias and were assigned qualityscores of fair or good, respectively. Strength of evidence(low, moderate, high, or insufcient) was determined sim-ilarly (17). Five types of data were abstracted from eachincluded study: study design, population evaluated, rFVIIadosing and administration, outcomes assessed, and study funding. Disagreements were resolved by discussion and, when necessary, review by a third author.

Data Synthesis and Analysis We summarized mortality, thromboembolism, and

other outcome rates for included studies. We consideredstudies eligible for meta-analysis if they were good- or fair-quality RCTs or good-quality observational studies and

Review Effectiveness of Off-Label Use of Recombinant Factor VIIa

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had similar interventions and patient populations. We didmeta-analyses when there were at least 2 studies of fair orbetter quality, including at least 1 of good quality.

The ICH RCTs had several intervention groups in which varying doses of rFVIIa were compared with a singlecontrol group. For these, we used a least-square xed-

effects model, a standard meta-analytic methodology forsynthesizing studies of this design (see the GleserOlkinmodel [2628]). We did meta-analyses by using bothxed-effects and random-effects models for sensitivity test-ing. We calculated standardized mean differences for per-centage of hematoma expansion, the only continuous vari-able analyzed. For dichotomous outcomes, we calculated 2effect-size metrics: risk differences (RDs) and arcsine stan-dardized mean differences (29). Results from these metrics were consistent. For ease of interpretation and because out-come rates were similar across studies (such that disadvan-tages of the RD metric were minimized), only RDs arereported here. We did meta-analytic calculations with theR statistics package, version 2.11.1 (www.r-project.org), by using a modied meta package (Guido Schwarzer, [email protected], version 1.6-0). Although we did assess-ments of heterogeneity by using theQ and I 2 statistics, weexpected these to be nonsignicant if too few studies wereincluded in each meta-analytic calculation. In that case,differences in ndings between the xed- and random-effects analyses were expected to highlight the presence of heterogeneity.

Because the literature suggested a doseresponse rela-tionship between rFVIIa and certain outcomes, particularly arterial thromboembolism, and the ICH RCTs reported

outcomes separately for several rFVIIa doses and arterialversus venous thromboemboli, we chose a priori to analyzethese data according to low, medium, and high doses (40mcg/kg, 40 but 120 mcg/kg, and 120 mcg/kg) andarterial versus venous thromboembolic outcomes. Doseresponse analyses were not possible for other indicationsbecause there were too few patients at specic dosages,dosages were unclear, or outcomes were not reported by dosage.Role of the Funding Source

Primary funding for the project was provided by the AHRQ, with additional support from the National Heart,

Lung, and Blood Institute and the Palo Alto MedicalFoundation Research Institute. Although the AHRQ formu-lated the initial study questions, the funding sources otherwisehad no role in the design and conduct of this study or in thecollection, management, analysis, or interpretation of thedata. The AHRQ reviewed the manuscript but did not assistin its preparation. The funding sources had no role in thedecision to submit the manuscript for publication.

RESULTSOur searches identied 6191 potentially relevant arti-

cles, of which 62 articles reporting on 64 studies met in-

clusion criteria ( Appendix Figure, available at www.annals.org). Of these, 26 studies (16 RCTs [30 43], 10comparative observational studies [4453]) are included inthe comparative effectiveness review (Table). Most hadsmall-to-moderate sample sizes (for patients who receivedrFVIIa, mean, 80; median, 44; range, 6 to 573). There was

great variability in doses of rFVIIa administered (range, 5to 400 mcg/kg). Thirty-eight additional studies (16 poor-quality comparative [5469] and 22 noncomparative [7091] observational studies) were included in the harms anal-yses. Overall, no studies compared rFVIIa with predecessorproducts that might be considered alternatives for someindications (for example, activated prothrombin complexconcentrates). Instead, the RCTs examined rFVIIa versusplacebo and the comparative observational studies com-pared it with usual care. There were few fair- or good-quality studies within any indication (Table) (6). Random-ized, controlled trials were generally of better quality thancomparative observational studies: Only 13% (2 of 16) of RCTs (41, 42) were of poor quality, whereas 62% (16 of 26) of the comparative observational studies (5469) wereof poor quality. All observational studies that were deter-mined to be of poor quality lacked appropriate methods togenerate comparability of groups or control for confound-ing. The small number of studies for any given indicationprecluded the use of funnel plots or other approaches forevaluation of publication bias. The manufacturer of rFVIIa, Novo Nordisk (Bagsvrd, Denmark), sponsoredmost of the RCTs.

Effectiveness Review Outcomes

The Table summarizes the key characteristics of thestudies providing comparative effectiveness outcomedata, along with their quality, strength of evidence, andconclusions. AlthoughFigure 1 summarizes the mortal-ity and thromboembolic event risk differences in theindividual studies, few of these studies were powered todistinguish important differences between treatmentgroups for these direct end points. Instead, they usedindirect end points (for example, transfusion require-ments) as primary outcomes. For all indications, quali-tative sensitivity analyses suggest that poor-quality com-parative observational studies (those not reviewed indepth in the effectiveness review but included in theharms analysis [ Appendix Tables 1 to 12, available at www.annals.org]) had results consistent with those re-ported for each indication for the RCTs and higher-quality observational studies (6). In the sections thatfollow, we present the benets and harms associated with use of rVIIa by specic indication. In all cases in which meta-analyses were done, the results of the xed-effects and random-effects models were virtually identi-cal and were in agreement on all determinations of sig-nicant versus nonsignicant ndings (that is, thosethat crossed the null), indicating the presence of littleheterogeneity among included studies. We report results

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Table. In-Depth Assessment of Studies in Effectiveness Review: Outcomes, Strength of Evidence, and Conclusions*

Study, Year (Reference) TotalRCTs or OBS, n

TotalStudies, byQuality, n

Total Patients,by Group, n

Outcome Strength ofEvidence

Range of Effect Sizesfor Risk per Period, by

Group

Conclusions (Associationof Use of rFVIIa vs. UsualCare)

rFVIIaGroup

UsualCareGroup

rFVIIaGroup

UsualCareGroup

Intracranial hemorrhageMayer et al, 2005 (30) and

2008 (33)RCT: 4 Good: 2 968 384 Mortality Moderate 0.080.22 0.130.29 No effect on mortality

(Figure 3)Mayer et al, 2005 (31) and

2006 (32)Fair: 2 Arterial TE events Moderate 0.040.11 00.13 Increased rate of arterial

TE events (Figure 3)Ilyas et al, 2008 (44) OBS: 1 Fair: 1 Poor functional

statusModerate 0.440.53 0.460.69 No effect on poor

functional statusPercentage of

hematomaexpansion

Moderate 479 1129 Decrease in percentage ofhematoma expansion

Cardiac surgeryGill et al, 2009 (35) RCT: 2 Good: 1 251 216 Mortality Low 00.33 0.060.33 No effect on mortality

(Figure 3)Diprose et al, 2005 (34) Fair: 1 TE events Moderate 00.22 00.20 Increased rate of TE events

(Figure 3)

Karkouti et al, 2005 (45), andGelsomino et al, 2008 (46) OBS: 4 Good: 2 RBCs transfused(units) Low 09.1 217 Possible reduction in RBCtransfusion requirementsvon Heymann et al, 2005 (47),

and Tritapepe et al, 2007 (48)Fair: 2 ICU length of stay

(d)Low 2.514 118.5 Unclear effect on ICU

length of stay

Body traumaHauser et al, 2010 (37) RCT: 4 Good: 2 746 900 Mortality Moderate 0.070.31 00.51 N o effect on mortality

(Figure 3)Boffard et al, 2005 (36) Fair 2 TE events Moderate 0.030.20 00.14 No effect on TE event rate

(Figure 3)Rizoli et al, 2006 (49); Fox et al,

2009 (50); and Wade et al,2010 (51)

OBS: 3 Fair: 3 ARDS Moderate 00.06 0.040.16 Decrease in rate of ARDS(Figure 3)

RBCs transfused(units)

Moderate 5.016.0 6.814.0 Unclear effect on RBCtransfusion requirements

Brain traumaNarayan et al, 2008 (38) RCT: 1 Fair: 1 79 53 Mortality Low 0.120.33 0.110.53 No effect on mortality

TE events Low 0.150.22 0.080.18 No effect on TE event rateStein et al, 2008 (52) OBS: 1 Fair: 1 Absolute hematomaexpansion (mL)

Low 7.0 10.4 No decrease in hematomagrowth

Liver transplantationLodge et al, 2005 (39), and

Planinsic et al, 2005 (40)RCT: 4 Fair: 2 215 117 Mortality Low 00.08 00.02 No effect on mortality

Pugliese et al, 2007 (41), andLiu et al, 2009 (42)

Poor: 2 TE events Low 00.22 00.16 No effect on TE event rate

Hendriks et al, 2001 (53) OBS: 1 Fair: 1 RBCs transfused(units)

Low 1.213.0 2.311.1 Possible reduction in RBCtransfusion requirements

OR time (min) Low 268554 432598 No reduction in OR timeICU length of stay

(d)Low 3.04.8 3.05.2 No reduction in ICU

length of stay

ProstatectomyFriederich et al, 2003 (43) RCT: 1 Fair: 1 24 12 Mortality Insufficient 0 0 Cannot comment because

of limited events

TE events Insufficient 00.13 0 Cannot comment becauseof limited eventsRBCs transfused

(units)Insufficient 00.6 1.5 Reduction in RBC

transfusion requirementsOR time (min) Insufficient 120126 180 Reduction in OR t ime

ARDS acute respiratory distress syndrome; ICU intensive care unit; OBS comparative observational study; OR operating room; RBC red blood cell; RCTrandomized, controlled trial; rFVIIa recombinant factor VIIa; TE thromboembolic.* The effectiveness review evaluates in depth all RCTs (3043) and fair- or better-quality comparative observational studies (4453). Strength of evidence is based on sco within 4 evidence domains (risk for bias, consistency, directness, and precision) and is rated as low, moderate, high, or insufcient. Outcome is given as a range of rates, unless otherwise stated. Each outcome range encompasses the lowest and highest rate per unit measured across all studies and, as should not be used to directly compare between the rFVIIa and usual care groups. Direct comparisons between groups are described in detail in the main report and summarized in the conclusions column. Poor functional status is a modied Rankin scale score of 4 to 6.




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from the xed-effects models. Unless otherwise noted,the low strength of evidence critically limits our ability to draw conclusions about the comparative effectivenessof rFVIIa and usual care.

ICH Identied RCTs examined only intracerebral hemor-rhage, rather than other forms of ICH (for example, sub-dural hematoma). Four RCTs (3033) and 1 comparativeobservational study (44) examined the use of rFVIIa in 968intervention patients (Table). Notably, although the RCTsexcluded patients receiving oral anticoagulation, all of thepatients in the 1 comparative observational study that metinclusion criteria were receiving oral anticoagulantshalf of whom had intracerebral hemorrhage and the other half had subdural hematoma. The meta-analyses found no evi-dence of effect on mortality of rFVIIa at any dosing level(Figure 2 and Appendix Tables 1 to 3) or poor functionaloutcome (as measured by the modied Rankin scale) (RDfor low dose, 0.02 [95% CI, 0.09 to 0.05]; mediumdose, 0.03 [CI, 0.10 to 0.04]; and high dose, 0.04[CI, 0.15 to 0.08]) compared with usual care. However,there was an increased rate of arterial thromboembolism with rFVIIa for the medium- and high-dose groups (Figure3). Use of rFVIIa signicantly decreased relative hematomaexpansion at all doses (standardized mean difference forlow dose, 0.15 [CI, 0.29 to 0.00]; medium dose,

0.24 [CI, 0.39 to 0.10]; and high dose, 0.33 [CI,0.58 to 0.09]). On statistical testing, there was no ev-

idence of dose effect for any end point, including mortality

and arterial thromboembolism (6). Thus, moderatestrength of evidence suggests that the use of rFVIIa forpatients with ICH who were not receiving oral anticoagu-lation yields no signicant benet for mortality or func-tional outcome but is associated with an increased risk forarterial thromboembolism.

Cardiac Surgery Two RCTs (34, 35) and 4 comparative observational

studies (4548) of 251 adult cardiac surgery patients re-ceiving rFVIIa met inclusion criteria, of which the 2 RCTs

and 2 of the observational studies (45, 46) were of suf-cient quality for meta-analysis. One RCT assessed prophy-lactic rFVIIa use at the conclusion of complex, noncoro-nary artery bypass grafting surgeries (34); the other studiesevaluated treatment for postoperative bleeding. However,the timing and context of rFVIIa administration was sim-ilar for all studies because bleeding is common after com-plex, noncoronary artery bypass grafting surgery, andrFVIIa was given after cardiopulmonary bypass in all cases.Thus, we considered it appropriate to combine these stud-ies. In meta-analyses, we found no effect of rFVIIa onmortality compared with usual care but an increased risk for thromboembolism (Figures 2 and 3 and Appendix Ta-

ble 4). Red blood cell transfusion requirements were pos-sibly reduced with rFVIIa, but the trend was apparent only across higher-quality studies ( Appendix Table 5). Resultsabout length of stay in the intensive care unit were notconsistent. In summary, current evidence of moderatestrength (for thromboembolic events) or low strength (forall other outcomes) suggests no mortality benet, but thatrFVIIa use increases the risk for thromboembolism.

Figure 1. Mortality and thomboembolic event riskdifferences (rFVIIa minus usual care) for indications with atleast 2 comparative studies included in the effectivenessreview.

M o r

t a l i t y

R i s k

D i f f e r e n c e

ICH CardiacSurgery

BodyTrauma

BrainTrauma

Liver Transplantation

0.25

0.20

0.15

0.10

0.05

0.00

0.05

0.10

0.15

T E E v e n

t R i s k D i f f e r e n c e

0.15

0.10

0.05

0.00

0.05

0.10

0.15

0.20

Indications with 2 or more comparative studies are included in thegure: ICH (3033, 44), cardiac surgery (34, 35, 4548), body trauma (36, 37, 4951), brain trauma (38, 52), and liver transplan-tation (39 42, 53). Each circle represents a study. Larger circlescorrespond to larger studies, shaded circles represent studies on treat-ment use of rFVIIa, and open circles represent studies on prophylac-tic use of rFVIIa. Intracranial hemorrhage outcomes here reect totalTE events in contrast to the arterial TE events assessed in the meta-analyses. For cardiac surgery, 3 study circles overlap at the 0 abscissafor mortality risk, and 2 similarly overlap for TE event risk. ICHintracranial hemorrhage; rFVIIa recombinant factor VIIa; TEthromboembolic.




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Body TraumaFour RCTs (published in 2 articles that both report

on 1 blunt and 1 penetrating trauma trial) (36, 37) and3 comparative observational studies (4951) assessed746 patients who received rFVIIa. Two RCTs (36) cen-

sored patients who died within 48 hours of injury foranalyses of transfusion requirementsa critical limita-tion of this literaturebut report on the end points of mortality, thromboembolic events, and the acute respi-ratory distress syndrome (ARDS) in all patients. Inmeta-analyses of the 4 RCTs, we found no effect of rFVIIa on mortality or thromboembolism but a signi-cant reduction in ARDS (Figures 2 and 3 and Appendix Table 6 ). Use of rFVIIa reduced transfusion require-ments in all 4 RCTs when all patients were included inthe analysis (that is, including previously censored pa-tients), but the decrease was signicant in only 1 RCT(37) ( Appendix Table 7). The observational studies did

not report usable comparative data on this outcome.Overall, available evidence of moderate strength identi-es no increased risk for thromboembolic events, a re-duced risk for ARDS, and no difference in mortality.

Brain TraumaOne RCT (38) and 1 comparative observational study

(52) evaluated 79 patients who had traumatic brain injury and received rFVIIa. The observational study included pa-tients receiving oral anticoagulation, whereas the RCT ex-cluded them and also patients for whom neurosurgery was planned. On systematic review, we found no effectof rFVIIa on mortality or thromboembolic events (RD[rFVIIa minus usual care] for mortality, 0 in the RCT and

0.2 in the observational study; RD for thromboembolicevents, 0.07 and 0.05, respectively) (Figure 1 and Appen-dix Table 8). In addition, rFVIIa use did not inuence

Figure 2. Meta-analysis of mortality associated with off-label use of rFVIIa for ICH, adult cardiac surgery, and body trauma inRCTs and good-quality observational studies.

Study, Year (Reference) rFVIIaEvents/Total, n/n

Usual CareEvents/Total, n/n

ICH, low doseMayer et al, 2005 (30)Mayer et al, 2005 (31)Mayer et al, 2006 (32)Mayer et al, 2008 (33)

CombinedICH, medium dose

Mayer et al, 2005 (30)Mayer et al, 2005 (31)Mayer et al, 2006 (32)Mayer et al, 2008 (33)

CombinedICH, high dose

Mayer et al, 2005 (30)Mayer et al, 2005 (31)

CombinedCardiac surgery

Diprose et al, 2005 (34)Gill et al, 2009 (35)Karkouti et al, 2005 (45)Gelsomino et al, 2008 (46)

CombinedBody trauma

Boffard et al, 2005 (36) (blunt)Hauser et al, 2010 (37) (blunt)Boffard et al, 2005 (36) (penetrating)Hauser et al, 2010 (37) (penetrating)

Combined

19/1081/187/24

50/276426

17/920/60/8

62/297403

20/1032/12115

0/910/103

7/512/40203

30/6924/21829/708/44401

28/962/111/8

51/268383

28/962/111/8

51/268383

28/962/11107

1/104/697/513/40170

35/7426/24228/645/38418

RD (95% CI)

0.12 (0.23 to 0.00)0.13 (0.38 to 0.13)0.17 (0.13 to 0.46)

0.01 (0.07 to 0.06)0.03 (0.09 to 0.02)

0.11 (0.23 to 0.01)0.18 (0.48 to 0.12)0.12 (0.41 to 0.16)0.02 (0.05 to 0.08)

0.02 (0.08 to 0.04)

0.10 (0.22 to 0.02)0.02 (0.33 to 0.30)0.02 (0.11 to 0.07)

0.10 (0.34 to 0.14)0.04 (0.04 to 0.12)0.00 (0.13 to 0.13)

0.02 (0.13 to 0.08)0.01 (0.05 to 0.06)

0.04 (0.20 to 0.12)0.00 (0.05 to 0.06)

0.02 (0.19 to 0.14)0.05 (0.11 to 0.21)0.00 (0.05 to 0.05)

RD (95% CI)Favors rFVIIa Favors Usual Care

0.4 0.2 0 0.2 0.4

For ICH, all studies are RCTs (3033) and meta-analyses are done according to dosing category (low, medium, and high). For cardiac surgery, thstudies by Diprose and colleagues (34) and Gill and coworkers (35) are RCTs, whereas those by Karkouti and colleagues (45) and Gelsomino acoworkers (46) are observational studies. For body trauma, all studies are RCTs (36, 37). ICHintracranial hemorrhage; RCT randomized,controlled trial; RD risk difference; rFVIIa recombinant factor VIIa.




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hematoma growth but was associated with a reduction intime to neurosurgical intervention (that is, by more quickly normalizing the international normalized ratio) in the ob-servational study, the 1 study that evaluated this outcome.In summary, current evidence of low strength is too lim-ited to compare the harms and benets of rFVIIa.

Liver TransplantationFour RCTs (3942) and 1 comparative observational

study (53) evaluated 215 patients with Child class B or C

cirrhosis who received prophylactic rFVIIa on initiation of liver transplantation. On systematic review, we found noeffect of rFVIIa on mortality or thromboembolism (RDrange [rFVIIa minus usual care] for mortality, 0 to 0.01;RD range for thromboembolic events, 0.03 to 0.17)(Figure 1 and Appendix Table 9). There was a trend across

studies toward reduced red blood cell transfusion require-ments with prophylaxis, but neither operating room timenor length of stay in the intensive care unit was reduced( Appendix Table 10). Thus, available evidence of low

Figure 3. Meta-analysis of thromboembolic events and the acute respiratory distress syndrome associated with off-label use ofrFVIIa for some indications in RCTs and good-quality observational studies.

Study, Year (Reference) rFVIIaEvents/Total, n/n

Usual CareEvents/Total, n/nThromboembolic events

ICH, low dose


CombinedICH, medium dose


CombinedICH, high dose

Mayer et al, 2005 (30)Mayer et al, 2005 (31)

Combined

Cardiac surgeryDiprose et al, 2005 (34)Gill et al, 2009 (35)Karkouti et al, 2005 (45)Gelsomino et al, 2008 (46)

CombinedBody trauma


Combined

6/1083/180/24

15/265415

2/920/60/8

27/293399

8/1030/12115

2/97/1038/512/40203

2/6945/218

4/702/44401

0/960/111/8

12/263378

0/960/111/8

12/263378

0/960/11107

2/101/695/510/40170

3/7435/242

3/645/38418

RD (95% CI)

0.06 (0.01 to 0.10)0.17 (0.04 to 0.37)0.12 (0.37 to 0.12)0.01 (0.03 to 0.05)

0.02 (0.00 to 0.05)

0.02 (0.01 to 0.06)0.00 (0.22 to 0.22)

0.12 (0.41 to 0.16)0.05 (0.00 to 0.09)0.03 (0.01 to 0.06)

0.08 (0.02 to 0.13)0.00 (0.15 to 0.15)

0.06 (0.01 to 0.11)

0.02 (0.35 to 0.39)0.05 (0.00 to 0.11)

0.06 (0.07 to 0.19)0.05 (0.03 to 0.13)

0.05 (0.01 to 0.10)

0.01 (0.07 to 0.05)0.06 (0.01 to 0.13)0.01 (0.06 to 0.09)

0.09 (0.21 to 0.04)0.01 (0.03 to 0.04)

The acute respiratory distress syndromeBody trauma


Combined

3/698/2184/700/44401

12/7418/242

5/643/38418

0.12 (0.22 to 0.02)0.04 (0.08 to 0.00)0.02 (0.11 to 0.06)0.08 (0.17 to 0.02)

0.05 (0.08 to 0.02)

RD (95% CI)

Favors rFVIIa Favors Usua l Care

0.4 0.2 0 0.2 0.4

For ICH, all studies are RCTs (3033), meta-analyses are done according to dosing category (low, medium, and high), and analyses of thromboemboevents are for arterial events only. For cardiac surgery, the studies by Diprose and colleagues (34) and Gill and coworkers (35) are RCTs, whereas thby Karkouti and colleagues (45) and Gelsomino and coworkers (46) are observational studies, and the meta-analyses of thromboembolic events evaluall events (both arterial and venous). For body trauma, all studies are RCTs (36, 37), and the meta-analyses of thromboembolic events evaluate all eveICH intracranial hemorrhage; RCT randomized, controlled trial; RD risk difference; rFVIIa recombinant factor VIIa.




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Grant Support: By the Agency for Healthcare Research and Quality,U.S. Department of Health and Human Services, under contract 290-02-0017. Dr. Owens was supported by the U.S. Department of Veterans Affairs. This research also was supported by training grants from the Na-tional Heart, Lung, and Blood Institute (RSS, K24HL086703) and the Palo Alto Medical Foundation Research Institute.

Potential Conflicts of Interest: Drs. Yank, Logan, and Bravata; Ms.Sundaram; and Ms. McDonald:Grant (money to institution):Agency forHealthcare Research and Quality. Dr. Staudenmayer:Employment:Stan-ford Hospital. Dr. Owens: Support for travel to meetings for the study or other purposes:Agency for Healthcare Research and Quality;Grant (money to institution):Agency for Healthcare Research and Quality;Con-sultancy:sano-aventis, Generation Health. Dr. Stafford:Expert testi-mony: Mylan Pharmaceuticals. Disclosures can also be viewed at www .acponline.org/authors/icmje/ConictOfInterestForms.do?msNum M10-2333.

Requests for Single Reprints: Veronica Yank, MD, Stanford Preven-tion Research Center, Stanford University, Medical School Ofce Build-ing X312, 251 Campus Drive, Stanford, CA 94304-5411; e-mail, vyank

@stanford.edu.

Current author addresses and author contributions are available at www .annals.org.

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with traumatic intracranial bleeding: dening the role of recombinant factor VIIa. J Trauma. 2007;63:725-32. [PMID: 18089997]90. Flower O, Phillips LE, Cameron P, Gunn K, Dunkley S, Watts A, et al.Recombinant activated factor VII in liver patients: a retrospective cohort study from Australia and New Zealand. Blood Coagul Fibrinolysis. 2010;21:207-15.[PMID: 20182351]91. Jarosz K, Czuprynska M, Andrzejewska J, Wasilewicz MP, Post M, Lu-bikowski J, et al.Administration of a recombinant factor Vlla in patients under-

going liver transplantation for fulminant hepatic failure. Transplant Proc. 2009;41:3088-90. [PMID: 19857684]92. Friedrich JO. Recombinant activated factor VII for acute intracerebral hem-orrhage [Letter]. N Engl J Med. 2005;352:2133-4. [PMID: 15901870]93. Logan AC, Yank V, Stafford RS.Off-label use of recombinant factor vlla inU.S. hospitals: analysis of hospital discharge records. Ann Intern Med. 2011;154:516-22.94. Physicians Desk Reference. 63rd ed. Montvale, NJ: Medical Economics;2009.95. Squizzato A, Ageno W.Recombinant activated factor VII as a general hae-mostatic agent: evidence-based efcacy and safety. Curr Drug Saf. 2007;2:155-61. [PMID: 18690962]96. Hsia CC, Chin-Yee IH, McAlister VC. Use of recombinant activated factorVII in patients without hemophilia: a meta-analysis of randomized control trials. Ann Surg. 2008;248:61-8. [PMID: 18580208]97. Pohar S, Tsakonas E, Murphy G, Anderson D, Carney D, Moltzan C, et al.Recombinant activated factor VII in treatment of hemorrhage unrelated to he-mophilia: a systematic review and economic evaluation. Technology report num-ber 118. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2009.98. Birchall J, Stanworth SJ, Duffy MR, Doree CJ, Hyde C. Evidence for theuse of recombinant factor VIIa in the prevention and treatment of bleeding inpatients without hemophilia. Transfus Med Rev. 2008;22:177-87. [PMID:18572094]99. Johansson PI. Off-label use of recombinant factor VIIa for treatment of haemorrhage: results from randomized clinical trials. Vox Sang. 2008;95:1-7.[PMID: 18435677]100. Lin Y, Stanworth S, Birchall J, Doree C, Hyde C. Use of recombinantfactor VIIa for the prevention and treatment of bleeding in patients withouthemophilia: a systematic review and meta-analysis. CMAJ. 2011;183:E9-19.[PMID: 21078742]101. Yuan ZH, Jiang JK, Huang WD, Pan J, Zhu JY, Wang JZ. A meta-

analysis of the efcacy and safety of recombinant activated factor VII for patients with acute intracerebral hemorrhage without hemophilia. J Clin Neurosci. 2010;17:685-93. [PMID: 20399668]102. Duchesne JC, Mathew KA, Marr AB, Pinsky MR, Barbeau JM, McSwainNE. Current evidence based guidelines for factor VIIa use in trauma: the good,the bad, and the ugly. Am Surg. 2008;74:1159-65. [PMID: 19097529]103. Patanwala AE. Factor VIIa (recombinant) for acute traumatic hemorrhage. Am J Health Syst Pharm. 2008;65:1616-23. [PMID: 18714107]104. Nishijima DK, Zehtabchi S. Evidence-based Emergency Medicine/Criti-cally Appraised Topic. The efcacy of recombinant activated factor VII in severetrauma. Ann Emerg Med. 2009;54:737-744.e1. [PMID: 19285753]105. Perel P, Roberts I, Shakur H, Thinkhamrop B, Phuenpathom N, Yut-thakasemsunt S. Haemostatic drugs for traumatic brain injury. Cochrane Data-base Syst Rev. 2010:CD007877. [PMID: 20091656]106. Warren O, Mandal K, Hadjianastassiou V, Knowlton L, Panesar S, JohnK, et al. Recombinant activated factor VII in cardiac surgery: a systematic review.

Ann Thorac Surg. 2007;83:707-14. [PMID: 17258029]107. Karkouti K, Beattie WS, Crowther MA, Callum JL, Chun R, Fremes SE,et al. The role of recombinant factor VIIa in on-pump cardiac surgery: proceed-ings of the Canadian Consensus Conference. Can J Anaesth. 2007;54:573-82.[PMID: 17602044]108. Dunning J, Versteegh M, Fabbri A, Pavie A, Kolh P, Lockowandt U, et al;EACTS Audit and Guidelines Committee. Guideline on antiplatelet and anti-coagulation management in cardiac surgery. Eur J Cardiothorac Surg. 2008;34:73-92. [PMID: 18375137]




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Current Author Addresses: Drs. Yank and Stafford: Stanford Preven-tion Research Center, Stanford University, Medical School Ofce Build-ing X312, 251 Campus Drive, Stanford, CA 94304-5411.Mr. Tuohy: 433 South 45th Street, Philadelphia, PA 19104.Dr. Logan: Division of Blood and Marrow Transplantation, StanfordUniversity School of Medicine, 269 West Campus Drive, CCSR 2200,Stanford, CA 94305.

Dr. Bravata: Castlight Health, 685 Market Street, #300, San Francisco,CA 94105.Dr. Staudenmayer: 300 Pasteur Drive, H3980, Stanford, CA 94305.Ms. Eisenhut: 1027 Amarillo Avenue, Palo Alto, CA 94303.Ms. Sundaram, Ms. McDonald, and Dr. Owens: Center for HealthPolicy, Center for Primary Care and Outcomes Research, Stanford Uni-versity, 117 Encina Commons, Stanford, CA 94305-6019.Dr. McMahon: Apartment 8, Summereld, Irishtown Road, Dublin 4,Ireland.Dr. Olkin: 950 Lathrop Place, Stanford, CA 94305.

Author Contributions: Conception and design: V. Yank, C.V. Tuohy,D.M. Bravata, V. Sundaram, I. Olkin, K.M. McDonald, D.K. Owens,

R.S. Stafford. Analysis and interpretation of the data: V. Yank, C.V. Tuohy, A.C.Logan, D.M. Bravata, K. Staudenmayer, R. Eisenhut, V. Sundaram,D. McMahon, I. Olkin, D.K. Owens, R.S. Stafford.Drafting of the article: V. Yank, D.M. Bravata, D. McMahon, I. Olkin,R.S. Stafford.

Critical revision of the article for important intellectual content:V. Yank, C.V. Tuohy, A.C. Logan, D.M. Bravata, K. Staudenmayer,V. Sundaram, I. Olkin, K.M. McDonald, D.K. Owens, R.S. Stafford.Final approval of the article: V. Yank, C.V. Tuohy, K. Staudenmayer,V. Sundaram, D. McMahon, I. Olkin, K.M. McDonald, D.K. Owens,R.S. Stafford.Provision of study materials or patients: R.S. Stafford.

Statistical expertise: D. McMahon, I. Olkin, D.K. Owens.Obtaining of funding: I. Olkin, K.M. McDonald, D.K. Owens, R.S.Stafford. Administrative, technical, or logistic support: C.V. Tuohy, V. Sundaram,K.M. McDonald, D.K. Owens, R.S. Stafford.Collection and assembly of data: V. Yank, C.V. Tuohy, A.C. Logan,R. Eisenhut, V. Sundaram, R.S. Stafford.

109. Nascimento B Jr, Tien H, Pinto R, et al. Dosage of factor VIIa (rFVIIa)and mortality in bleeding trauma patients. J Trauma. 2008;64:558.110. Spinella PC, Perkins JG, McLaughlin DF, Niles SE, Grathwohl KW,Beekley AC, et al.The effect of recombinant activated factor VII on mortality incombat-related casualties with severe trauma and massive transfusion. J Trauma.2008;64:286-93. [PMID: 18301188]111. Lodge JP, Jonas S, Jones RM, Olausson M, Mir-Pallardo J, Soefelt S, et al;

rFVIIa OLT Study Group. Efcacy and safety of repeated perioperative doses of recombinant factor VIIa in liver transplantation. Liver Transpl. 2005;11:973-9.[PMID: 16035095]112. Friederich PW, Henny CP, Messelink EJ, Geerdink MG, Keller T, KurthKH, et al. Effect of recombinant activated factor VII on perioperative blood lossin patients undergoing retropubic prostatectomy: a double-blind placebo-controlled randomised trial. Lancet. 2003;361:201-5. [PMID: 12547542]

Annals of Internal Medicine

W-178 19 April 2011 Annals of Internal Medicine Volume 154 Number 8 www.annals.org


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A p p e n

d i x T a b

l e 3 . I n d i r e c t

O u t c o m e s

i n C o m p a r a t i v e

S t u d i e s o f r F

V I I a U s e i n I n t r a c r a n i a l H e m o r r h a g e

S t u d y ,

Y e a r

( R e f e r e n c e

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S t u d y D e s i g n a n

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r F V I I a U s e

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( S D ) [ R a n g e

]

r F V I I a D o s e ,

m c g / k g

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S i z e ,

n

M e a n A g e

( S D ) [ R a n g e

] , y

R e l a t i v e H e m a t o m a E x p a n s i o n

( S D ) [ 9 5 % C I ]

, %

A b s o l u t e H e m a t o m a E x p a n s i o n

( S D ) [ 9 5 % C I ]

, m L

r F V I I a G r o u p

U s u a l

C a r e

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U s u a l

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r a n d o m i z e d , c o n t r o l l e d t r i a l ; r F V I I a

r e c o m b i n a n t f a c t o r V I I a .

* P v a

l u e s p r e s e n t e d a r e t h o s e r e p o r t e d b y t h e i n d i v i

d u a l s t u d i e s .

I n M a y e r e t a l ( 3 0 )

, 9 8 . 3 % C I i s u s e d .

T h e c o m p a r i s o n w a s s t a t i s t i c a l l y s i g n i c a n t a c c o r d i n g t o t h e p r e s p e c i e d B o n f e r r o n i - c o r r e c t e d t h r e s h o l d o f P

0 . 0 1 6 7 i n M a y e r e t a l ( 3 0 )

.

S t u d i e s d i d n o t m e e t i n c l u s i o n c r i t e r i a f o r d e t a i l e d r e v i e w i n t h e c o m p a r a t i v e e f f e c t i v e n e s s a n a l y s e s o w

i n g t o p o o r q u a l i t y b u t w e r e i n c l u d e d i n t h e q u a l i t a t i v e s e n s i t i v i t y a n a l y s e s d e s c r i b e d i n t h e E f f e c t i v e n e s s R e v i e w O u t c o m e s

s e c t i o n a n d t h e E v a l u a t i o n o f H a r m s s e c t i o n .

M e a n d o s e i n m g r a t h e r t h a n m c g / k g o f b o d y w e

i g h t

.

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l e 4 . M o r t a l i t y a n

d T h r o m

b o e m

b o l i c E v e n t s i n C o m p a r a t i v e

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d i a c

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d r F

V I I a

U s e

E x a c t o r

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( I Q R )

r F V I I a D o s e ,

m c g / k g

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n

M e a n A g e

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b o e m

b o l i c E v e n t R a t e *


U s u a l

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U s u a l

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t r e a t m e n t

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0 . 1 5 7

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t r e a t m e n t

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t r e a t m e n t

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t r e a t m e n t

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i n t e r q u a r t i l e r a n g e ; N R

n o t r e p o r t e d ; N S

n o t s i g n i c a n t ; R C T

r a n d o m i z e d , c o n t r o l l e d t r i a l ; r F V I I a

r e c o m b i n a n t f a c t o r V I I a .

* T h r o m b o e m b o l i c e v e n t r a t e s w e r e c a l c u l a t e d b y

d i v i

d i n g t h e n u m b e r o f t h r o m b o e m b o l i c e v e n t s b y t h e s a m p l e s i z e , n o t t h e n u m b e r o f p a t i e n t s w h o h a d t h r o m b o e m b o l i c e v e n t s . T h e r e f o r e , t h e r a t e s r e p o r t e d h e r e m a y d i f f e r

s l i g h t l y f r o m t h o s e r e p o r t e d i n e a c h s t u d y

. T h e t e s t s o f s t a t i s t i c a l s i g n i c a n c e p r e s e n t e d a r e t h o s e r e p o r t e d b y t h e i n d i v i

d u a l s t u d i e s a n d a r e n o t b a s e d o n t h e t h r o m b o e m b o l i c e v e n t r a t e s r e p o r t e d i n t h i s t a b l e .

P v a

l u e s p r e s e n t e d a r e t h o s e r e p o r t e d b y t h e i n d i v i

d u a l s t u d i e s .

D i p r o s e e t a l ( 3 4 ) e x c l u d e d 1 p a t i e n t w h o v i o l a t e d t h e s t u d y p r o t o c o l a f t e r r a n d o m i z a t i o n . T h i s p a t i e n t w a s n o t e v a

l u a t e d f o r m o r t a l i t y o r t h r o m b o e m b o l i c e v e n t s .

M e d i a n .

T h e h o s p i t a l m o r t a l i t y r a t e s a t 6 m o w e r e 0 . 5 8 3 i n t h e r F V I I a g r o u p a n d 0 . 4 1 7 i n t h e u s u a l c a r e

g r o u p .

S t u d i e s d i d n o t m e e t i n c l u s i o n c r i t e r i a f o r d e t a i l e d r e v i e w i n t h e c o m p a r a t i v e e f f e c t i v e n e s s a n a l y s e s o w i n g t o p o o r q u a l i t y b u t w e r e i n c l u d e d i n t h e q u a l i t a t i v e s e n s i t i v i t y a n a l y s e s d e s c r i b e d i n t h e E f f e c t i v e n e s s R e v i e w O u t c o m e s

s e c t i o n a n d t h e E v a l u a t i o n o f H a r m s s e c t i o n .

* * T h e s e d a t a w e r e e x t r a p o l a t e d a s t h e r a n g e o f p o s s i b l e m o r t a l i t y

f o r t h e u s u a l c a r e g r o u p , g i v e n t h e m o r t a l i t y r a t e s r e p o r t e d f o r t h e r F V I I a g r o u p a n d t h e g r o u p o f a l l p a t i e n t s c o m b i n e d .

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4-19-11 annals of internal medicine - systematic review of harms and benefits of factor viia

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