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Systematic Review: Benefits and Harms of In-Hospital Use of Recombinant Factor VIIa for Off-Label Indications FREE

Veronica 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
[+] Article and Author Information

From Stanford School of Medicine and Stanford University, Stanford, California; Palo Alto Medical Foundation Research Institute and Veterans Affairs Palo Alto Health Care System, Palo Alto, California; University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and Castlight Health, San Francisco, California.


Disclaimer: The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality, the U.S. Department of Health and Human Services, or the U.S. Department of Veterans Affairs.

Acknowledgment: The authors are grateful to David Johnston, Christopher D. Stave, and James L. Zehnder of Stanford University for their contributions to this effectiveness review.

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 National 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 for Healthcare Research and Quality. Dr. Staudenmayer: Employment: Stanford 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; Consultancy: sanofi-aventis, Generation Health. Dr. Stafford: Expert testimony: Mylan Pharmaceuticals. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-2333.

Requests for Single Reprints: Veronica Yank, MD, Stanford Prevention Research Center, Stanford University, Medical School Office Building X312, 251 Campus Drive, Stanford, CA 94304-5411; e-mail, vyank@stanford.edu.

Current Author Addresses: Drs. Yank and Stafford: Stanford Prevention Research Center, Stanford University, Medical School Office Building 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, Stanford University 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 Health Policy, Center for Primary Care and Outcomes Research, Stanford University, 117 Encina Commons, Stanford, CA 94305-6019.

Dr. McMahon: Apartment 8, Summerfield, 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.


Ann Intern Med. 2011;154(8):529-540. doi:10.7326/0003-4819-154-8-201104190-00004
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Background: Recombinant factor VIIa (rFVIIa), a hemostatic agent approved for hemophilia, is increasingly used for off-label indications.

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

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

Study Selection: Two reviewers independently screened titles and abstracts to identify clinical use of rFVIIa for the selected indications and identified all randomized, controlled trials (RCTs) and observational studies for full-text review.

Data Extraction: Two reviewers independently assessed study characteristics and rated study quality and indication-wide strength of evidence.

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. Arterial thromboembolism was increased with medium-dose rFVIIa use (risk difference [RD], 0.03 [95% CI, 0.01 to 0.06]) and high-dose rFVIIa use (RD, 0.06 [CI, 0.01 to 0.11]). For adult cardiac surgery, there was 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 thromboembolism, but there was a reduced risk for the acute respiratory distress syndrome (RD, −0.05 [CI, −0.02 to −0.08]). Mortality was higher in observational studies than in RCTs.

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

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

Primary Funding Source: Agency for Healthcare Research and Quality.

Recombinant factor VIIa (rFVIIa) is an expensive and potent procoagulant. The U.S. Food and Drug Administration (FDA) approved intravenous use of rFVIIa in 1999 for patients with hemophilia A or B and antibody inhibitors against standard-factor replacements. Recently, its use has expanded beyond these approved indications to encompass a wide range of in-hospital, off-label applications.

Off-label drug use refers to any application that deviates from FDA-approved use. The FDA drug-approval process mandates that randomized, clinical trials demonstrate efficacy 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 adoption of some therapies, the available evidence supporting it usually falls short of the rigor that accompanies FDA review. Even though the resulting uncertainty may be acceptable, concerns increase when off-label use is applied to conditions that are clinically distinct from approved indications or it is done frequently, is costly, or is associated with important side effects or harms.

The off-label use of rFVIIa for hospitalized patients has increased, despite concerns about efficacy and safety, including evidence suggesting an increased rate of thromboembolic events (15). Our comparative effectiveness review evaluates the benefits 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.

The 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 followed standardized protocols for data searches, extraction, quality assessments, and syntheses.

Data Sources and Searches
Searches

In collaboration with a research librarian, we developed individualized search strategies for 10 bibliographic databases from inception through 31 December 2010: PubMed, EMBASE, the Cochrane Library, ACP Journal Club, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, CMR, Health Technology Assessment, National Health Service Economic Evaluation Database, and BIOSIS. We contacted experts and reviewed bibliographies of identified systematic reviews, files supplied by the manufacturer, and the manufacturer's Web site. A librarian expert on gray literature (sources other than published materials indexed in bibliographic databases) searched regulatory sites, clinical trial registries, conference proceedings, and grant-funded and federally funded research sites and contacted authors of abstracts to determine 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 hospitalized patients with 5 off-label indications: ICH, cardiac surgery, trauma, liver transplantation, and prostatectomy. For inclusion, studies had to address direct or surrogate clinical outcomes. We did not contact authors about results that were not reported in their publications. We excluded studies published only as abstracts and studies of human factor VIIa or modified recombinant forms under development; studies on use of rFVIIa for on-label indications and rFVIIa applied to patients substantially similar to those for whom on-label indications are approved (for example, Glanzmann thrombasthenia); and studies whose outcome measures (for example, drug half-life) are not relevant to efficacy, effectiveness, or safety. Lastly, we reviewed the English-language abstracts and references of studies published in non-English languages. Among these, we identified 2 small comparative studies likely eligible for effectiveness review (randomized, controlled trial [RCT] of cardiac surgery [11 patients who received rFVIIa] [7] and comparative cohort study of brain trauma [7 who received rFVIIa] [8]) and 6 case series reports (range, 16 to 35 patients) (914) likely eligible for harms analyses if we had the capacity to do a full-text review. The RCT was used for sensitivity testing, with similar results to those reported 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 that such exclusions were unlikely to bias our findings because few articles were identified and the studies enrolled few patients.

Study Selection

Two reviewers independently screened titles and abstracts to identify clinical use of rFVIIa for the selected indications and identified all RCTs and observational studies for full-text review. For the effectiveness analyses, we included RCTs and comparative observational studies. We reviewed all RCTs in detail, whereas we reviewed only comparative observational studies of fair or good quality in detail. We used comparative observational studies of poor quality for qualitative sensitivity analyses. Patients from overlapping or duplicate articles reporting on the same patient population were included only once.

Although noncomparative studies are a less reliable source of evidence than comparative studies, they may report infrequent events not identified in RCTs (15). Given concerns about the possibility of clinically significant harms, we included registries and cohorts with at least 15 total patients in the harms analyses. We selected 15 patients as the minimum threshold because the risk for bias (for example, selective reporting) is probably increased in smaller reports. We also included the treatment groups of all comparative studies in the harms analyses.

Data Extraction and Quality Assessment

Two 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 evaluated by using well-established criteria (1625) and a predefined systematic approach described further in the AHRQ report (6). The quality criteria were specific to the study type and were used to assign each study a quality score from the ordinal scale of poor, fair, or good by using qualitative determinations rather than numerical scores. For RCTs, essential quality elements included appropriate randomization, allocation concealment, blinding, and absence of differential follow-up. For observational studies, essential quality elements included appropriate methods to generate comparability of groups and control for confounding, appropriate blinding, and absence of differential follow-up. Studies that did not achieve (or did not adequately report) these elements were assigned a quality score of poor. Studies that achieved these partially or fully were felt to have a lower risk for bias and were assigned quality scores of fair or good, respectively. Strength of evidence (low, moderate, high, or insufficient) was determined similarly (17). Five types of data were abstracted from each included study: study design, population evaluated, rFVIIa dosing 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 considered studies eligible for meta-analysis if they were good- or fair-quality RCTs or good-quality observational studies and had similar interventions and patient populations. We did meta-analyses when there were at least 2 studies of fair or better 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 single control group. For these, we used a least-square fixed-effects model, a standard meta-analytic methodology for synthesizing studies of this design (see the Gleser–Olkin model [2628]). We did meta-analyses by using both fixed-effects and random-effects models for sensitivity testing. We calculated standardized mean differences for percentage of hematoma expansion, the only continuous variable analyzed. For dichotomous outcomes, we calculated 2 effect-size metrics: risk differences (RDs) and arcsine standardized mean differences (29). Results from these metrics were consistent. For ease of interpretation and because outcome rates were similar across studies (such that disadvantages of the RD metric were minimized), only RDs are reported here. We did meta-analytic calculations with the R statistics package, version 2.11.1 (www.r-project.org), by using a modified meta package (Guido Schwarzer, sc@imbi.uni-freiburg.de, version 1.6-0). Although we did assessments of heterogeneity by using the Q and I2 statistics, we expected these to be nonsignificant if too few studies were included in each meta-analytic calculation. In that case, differences in findings between the fixed- and random-effects analyses were expected to highlight the presence of heterogeneity.

Because the literature suggested a dose–response relationship between rFVIIa and certain outcomes, particularly arterial thromboembolism, and the ICH RCTs reported outcomes separately for several rFVIIa doses and arterial versus venous thromboemboli, we chose a priori to analyze these data according to low, medium, and high doses (≤40 mcg/kg, >40 but <120 mcg/kg, and ≥120 mcg/kg) and arterial versus venous thromboembolic outcomes. Dose–response analyses were not possible for other indications because there were too few patients at specific 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 Medical Foundation Research Institute. Although the AHRQ formulated the initial study questions, the funding sources otherwise had no role in the design and conduct of this study or in the collection, management, analysis, or interpretation of the data. The AHRQ reviewed the manuscript but did not assist in its preparation. The funding sources had no role in the decision to submit the manuscript for publication.

Our searches identified 6191 potentially relevant articles, of which 62 articles reporting on 64 studies met inclusion criteria (Appendix Figure). Of these, 26 studies (16 RCTs [3043], 10 comparative observational studies [4453]) are included in the comparative effectiveness review (Table). Most had small-to-moderate sample sizes (for patients who received rFVIIa, mean, 80; median, 44; range, 6 to 573). There was great variability in doses of rFVIIa administered (range, 5 to 400 mcg/kg). Thirty-eight additional studies (16 poor-quality comparative [5469] and 22 noncomparative [7091] observational studies) were included in the harms analyses. Overall, no studies compared rFVIIa with predecessor products that might be considered alternatives for some indications (for example, activated prothrombin complex concentrates). Instead, the RCTs examined rFVIIa versus placebo and the comparative observational studies compared it with usual care. There were few fair- or good-quality studies within any indication (Table) (6). Randomized, controlled trials were generally of better quality than comparative observational studies: Only 13% (2 of 16) of RCTs (4142) were of poor quality, whereas 62% (16 of 26) of the comparative observational studies (5469) were of poor quality. All observational studies that were determined to be of poor quality lacked appropriate methods to generate comparability of groups or control for confounding. The small number of studies for any given indication precluded the use of funnel plots or other approaches for evaluation of publication bias. The manufacturer of rFVIIa, Novo Nordisk (Bagsværd, Denmark), sponsored most of the RCTs.

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Appendix Figure.
Summary of evidence search and selection.

CCTR = Cochrane Central Register of Controlled Trials; DARE = Database of Abstracts of Reviews of Effects; RCT = randomized, controlled trial; rFVIIa = recombinant factor VIIa.

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

The Table summarizes the key characteristics of the studies providing comparative effectiveness outcome data, along with their quality, strength of evidence, and conclusions. Although Figure 1 summarizes the mortality and thromboembolic event risk differences in the individual studies, few of these studies were powered to distinguish important differences between treatment groups for these direct end points. Instead, they used indirect end points (for example, transfusion requirements) as primary outcomes. For all indications, qualitative sensitivity analyses suggest that poor-quality comparative observational studies (those not reviewed in depth in the effectiveness review but included in the harms analysis [Appendix Tables 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12]) had results consistent with those reported for each indication for the RCTs and higher-quality observational studies (6). In the sections that follow, we present the benefits and harms associated with use of rVIIa by specific indication. In all cases in which meta-analyses were done, the results of the fixed-effects and random-effects models were virtually identical and were in agreement on all determinations of significant versus nonsignificant findings (that is, those that crossed the null), indicating the presence of little heterogeneity among included studies. We report results from the fixed-effects models. Unless otherwise noted, the low strength of evidence critically limits our ability to draw conclusions about the comparative effectiveness of rFVIIa and usual care.

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Figure 1.
Mortality and thomboembolic event risk differences (rFVIIa minus usual care) for indications with at least 2 comparative studies included in the effectiveness review.

Indications with 2 or more comparative studies are included in the figure: ICH (3033, 44), cardiac surgery (3435, 4548), body trauma (3637, 4951), brain trauma (38, 52), and liver transplantation (3942, 53). Each circle represents a study. Larger circles correspond to larger studies, shaded circles represent studies on treatment use of rFVIIa, and open circles represent studies on prophylactic use of rFVIIa. Intracranial hemorrhage outcomes here reflect total TE events in contrast to the arterial TE events assessed in the meta-analyses. For cardiac surgery, 3 study circles overlap at the 0 abscissa for mortality risk, and 2 similarly overlap for TE event risk. ICH = intracranial hemorrhage; rFVIIa = recombinant factor VIIa; TE = thromboembolic.

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Table Jump PlaceholderAppendix Table 1.  Mortality and Poor Functional Outcome on Modified Rankin Scale Score in Comparative Studies of rFVIIa Use in Intracranial Hemorrhage
Table Jump PlaceholderAppendix Table 2.  Thromboembolic Events (Arterial and Venous) in Comparative Studies of rFVIIa Use in Intracranial Hemorrhage
Table Jump PlaceholderAppendix Table 3.  Indirect Outcomes in Comparative Studies of rFVIIa Use in Intracranial Hemorrhage
Table Jump PlaceholderAppendix Table 4.  Mortality and Thromboembolic Events in Comparative Studies of rFVIIa Use in Cardiac Surgery
Table Jump PlaceholderAppendix Table 5.  Indirect Outcomes in Comparative Studies of rFVIIa Use in Adult Cardiac Surgery
Table Jump PlaceholderAppendix Table 6.  Mortality, Thromboembolic Events, and ARDS in Comparative Studies of rFVIIa Use in Body Trauma
Table Jump PlaceholderAppendix Table 7.  Indirect Outcomes in Comparative Studies of rFVIIa Use in Body Trauma
Table Jump PlaceholderAppendix Table 8.  Mortality, Thromboembolic Events, and Absolute Change in Hematoma Volume in Comparative Studies of rFVIIa Use in Brain Trauma
Table Jump PlaceholderAppendix Table 9.  Mortality and Thromboembolic Events in Comparative Studies of rFVIIa Use in Liver Transplantation
Table Jump PlaceholderAppendix Table 10.  Indirect Outcomes in Comparative Studies of rFVIIa Use in Liver Transplantation
Table Jump PlaceholderAppendix Table 11.  Mortality and Thromboembolic Events in RCTs on rFVIIa Use in Prostatectomy
Table Jump PlaceholderAppendix Table 12.  Indirect Outcomes in RCTs on rFVIIa Use in Prostatectomy
ICH

Identified RCTs examined only intracerebral hemorrhage, rather than other forms of ICH (for example, subdural hematoma). Four RCTs (3033) and 1 comparative observational study (44) examined the use of rFVIIa in 968 intervention patients (Table). Notably, although the RCTs excluded patients receiving oral anticoagulation, all of the patients in the 1 comparative observational study that met inclusion criteria were receiving oral anticoagulants—half of whom had intracerebral hemorrhage and the other half had subdural hematoma. The meta-analyses found no evidence of effect on mortality of rFVIIa at any dosing level (Figure 2 and Appendix Tables 1, 2, and 3) or poor functional outcome (as measured by the modified Rankin scale) (RD for low dose, −0.02 [95% CI, −0.09 to 0.05]; medium dose, −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 (Figure 3). Use of rFVIIa significantly decreased relative hematoma expansion at all doses (standardized mean difference for low 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 evidence of dose effect for any end point, including mortality and arterial thromboembolism (6). Thus, moderate strength of evidence suggests that the use of rFVIIa for patients with ICH who were not receiving oral anticoagulation yields no significant benefit for mortality or functional outcome but is associated with an increased risk for arterial thromboembolism.

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

For ICH, all studies are RCTs (30–33) and meta-analyses are done according to dosing category (low, medium, and high). For cardiac surgery, the studies by Diprose and colleagues (34) and Gill and coworkers (35) are RCTs, whereas those by Karkouti and colleagues (45) and Gelsomino and coworkers (46) are observational studies. For body trauma, all studies are RCTs (36, 37). ICH = intracranial hemorrhage; RCT = randomized, controlled trial; RD = risk difference; rFVIIa = recombinant factor VIIa.

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

For ICH, all studies are RCTs (3033), meta-analyses are done according to dosing category (low, medium, and high), and analyses of thromboembolic events are for arterial events only. For cardiac surgery, the studies by Diprose and colleagues (34) and Gill and coworkers (35) are RCTs, whereas those by Karkouti and colleagues (45) and Gelsomino and coworkers (46) are observational studies, and the meta-analyses of thromboembolic events evaluate all events (both arterial and venous). For body trauma, all studies are RCTs (3637), and the meta-analyses of thromboembolic events evaluate all events. ICH = intracranial hemorrhage; RCT = randomized, controlled trial; RD = risk difference; rFVIIa = recombinant factor VIIa.

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Cardiac Surgery

Two RCTs (3435) and 4 comparative observational studies (4548) of 251 adult cardiac surgery patients receiving rFVIIa met inclusion criteria, of which the 2 RCTs and 2 of the observational studies (4546) were of sufficient quality for meta-analysis. One RCT assessed prophylactic rFVIIa use at the conclusion of complex, noncoronary artery bypass grafting surgeries (34); the other studies evaluated treatment for postoperative bleeding. However, the timing and context of rFVIIa administration was similar for all studies because bleeding is common after complex, noncoronary artery bypass grafting surgery, and rFVIIa was given after cardiopulmonary bypass in all cases. Thus, we considered it appropriate to combine these studies. In meta-analyses, we found no effect of rFVIIa on mortality compared with usual care but an increased risk for thromboembolism (Figures 2 and 3 and Appendix Table 4). Red blood cell transfusion requirements were possibly reduced with rFVIIa, but the trend was apparent only across higher-quality studies (Appendix Table 5). Results about length of stay in the intensive care unit were not consistent. In summary, current evidence of moderate strength (for thromboembolic events) or low strength (for all other outcomes) suggests no mortality benefit, but that rFVIIa use increases the risk for thromboembolism.

Body Trauma

Four RCTs (published in 2 articles that both report on 1 blunt and 1 penetrating trauma trial) (3637) and 3 comparative observational studies (4951) assessed 746 patients who received rFVIIa. Two RCTs (36) censored patients who died within 48 hours of injury for analyses of transfusion requirements—a critical limitation of this literature—but report on the end points of mortality, thromboembolic events, and the acute respiratory distress syndrome (ARDS) in all patients. In meta-analyses of the 4 RCTs, we found no effect of rFVIIa on mortality or thromboembolism but a significant reduction in ARDS (Figures 2 and 3 and Appendix Table 6). Use of rFVIIa reduced transfusion requirements in all 4 RCTs when all patients were included in the analysis (that is, including previously censored patients), but the decrease was significant 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 identifies no increased risk for thromboembolic events, a reduced risk for ARDS, and no difference in mortality.

Brain Trauma

One RCT (38) and 1 comparative observational study (52) evaluated 79 patients who had traumatic brain injury and received rFVIIa. The observational study included patients receiving oral anticoagulation, whereas the RCT excluded them and also patients for whom neurosurgery was planned. On systematic review, we found no effect of 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 thromboembolic events, 0.07 and 0.05, respectively) (Figure 1 and Appendix Table 8). In addition, rFVIIa use did not influence hematoma growth but was associated with a reduction in time to neurosurgical intervention (that is, by more quickly normalizing the international normalized ratio) in the observational study, the 1 study that evaluated this outcome. In summary, current evidence of low strength is too limited to compare the harms and benefits of rFVIIa.

Liver Transplantation

Four 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 no effect of rFVIIa on mortality or thromboembolism (RD range [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 requirements with prophylaxis, but neither operating room time nor length of stay in the intensive care unit was reduced (Appendix Table 10). Thus, available evidence of low strength is too limited to compare the harms and benefits of rFVIIa.

Prostatectomy

There was 1 RCT on prophylactic use of rFVIIa in 24 patients having retropubic prostatectomy for prostate cancer or benign prostatic hypertrophy (92) (providing an insufficient strength of evidence for all outcomes). Mortality and thromboembolic events could not be evaluated because of limited events (0 deaths, 1 thromboembolic event) (Appendix Table 11). Red blood cell transfusion requirements and operating room time were significantly decreased with rFVIIa use (Appendix Table 12).

Evaluation of Harms: Data From RCTs Versus Comparative and Noncomparative Observational Studies

Unadjusted mortality rates among patients who received rFVIIa ranged widely from 0 to 0.87 (median, 0.17), and thromboembolism rates ranged from 0 to 0.39 (median, 0.09) (6). In general, mortality rates were lowest in RCTs and highest in observational studies, but the relationship between study type and thromboembolism rate was less clear (Figure 4). Randomized, controlled trials of ICH—which had the longest follow-up and most completely described ascertainment of harms—had mortality and thrombembolic event rates only slightly different from those in observational studies. The discrepancy between harms reported in RCTs versus observational studies was greater for other indications. There was no apparent correlation between rFVIIa dose and harms outcomes (6), which is similar to our effectiveness review finding for ICH of no dose effect. There also was no apparent relationship between age and harms outcomes (6), although it is notable that ages tended to cluster for a given indication, which may have made any relationship difficult to ascertain. Finally, there was no observable pattern between the likelihood of mortality and thromboembolism (6), which is similar to the effectiveness review findings for certain indications (ICH and cardiac surgery) of no effect of rFVIIa on mortality, despite an associated increase in thromboembolic events.

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Figure 4.
Harms analysis: weighted mortality and thromboembolic events in all RCTs and observational studies, by indication.

Harms analyses include patients who received recombinant factor VIIa from registries and cohorts (noncomparative observational studies) with at least 15 patients (ICH [7072], cardiac surgery [7383], body trauma [8487], brain trauma [8889], and liver transplantation [9091]), as well as patients from the treatment groups of all RCTs (3043) and comparative observational studies (4469), regardless of quality. For liver transplantation, the reported RCT rate of TE events is an underestimate, because 1 RCT (40) did not report venous events by group (treatment vs. placebo), so the events could not be tallied. For studies with overlapping data sets (e.g., the same registry patients being evaluated in a noncomparative study and a comparative observational study), the most complete data set for the outcome of interest was used. Comp Obs = comparative observational study; ICH = intracranial hemorrhage; Noncomp Obs = noncomparative observational study; RCT = randomized, controlled trial; TE = thromboembolic.

Grahic Jump Location

Available evidence indicates that in-hospital, off-label use of rFVIIa does not reduce mortality for any indication we evaluated. In contrast, use of rFVIIa increases the rate of thromboembolic events in ICH and cardiac surgery. Of the indications studied, the benefit–risk ratio may be most favorable for body trauma because rFVIIa use in this population is associated with a reduced risk for ARDS, although this finding must be placed in the context of no accompanying reduction in mortality. In addition, the strength of evidence is low or moderate for all outcomes, which precludes definitive conclusions. The harms analyses raise additional concerns by noting that mortality rates among patients receiving rFVIIa are generally greater in observational studies—in which patient groups more closely reflect unselected patient populations—compared with RCTs. Our analysis of data from nonfederal U.S. hospitals found that 97% of in-hospital use of rFVIIa was off-label, with most for ICH, cardiac surgery, and trauma indications (93). This increasingly frequent off-label use of rFVIIa is occurring despite its expense (at least $10 000 for a single 90-mcg/kg dose in a patient weighing 70 kg) (94), lack of mortality benefit, and growing evidence of associated harms.

Our systematic review in some cases extends the findings of previous reviews by incorporating data from comparative observational studies in the effectiveness review, assessing the effect of dosing level when possible and assessing harms across different study types known to have varying degrees of generalizability to real-world populations. We are able to provide indication-specific findings for disparate clinical applications, as well as an overview of use that identifies outcome patterns across indications, such as an increase in thromboembolism for some. Previous reviews that pooled data for several indications identified no mortality benefit with off-label rFVIIa use (2, 95100), and many reviews noted a nonsignificant increase in thromboembolism (2, 96)(98100) or, more recently, a significant increase (5), but none could provide indication-specific guidance. Regarding specific indications, a Cochrane review of ICH and hemostatic drug therapies, overwhelmingly rFVIIa, noted no mortality reduction but a nonsignificant increase in thromboembolism (3), whereas a more recent review by Yuan and colleagues (101) had the same findings as ours regarding a significantly increased risk for arterial thromboembolism without any attendant benefits for mortality or functional outcome. A meta-analysis of cardiac surgery observed no effect on mortality and a nonsignificant increase in perioperative stroke (4). For body trauma, 3 systematic reviews concluded that rFVIIa did not decrease mortality (102104). For brain trauma, a recent Cochrane review by Perel and coworkers (105) identified few studies and no mortality benefit. Other reviews were more supportive of rFVIIa, describing it as a “promising” therapy (106) or one that might reasonably be used as rescue therapy (107108) but did not do meta-analyses. Specific to harms analyses, O'Connell and colleagues (1) evaluated data from the FDA's Adverse Event Reporting System to document serious thromboembolic events after off-label rFVIIa use.

Our analysis has several limitations. First, the heterogeneity of included studies prevented us from pooling data across clinical indications. Second, we found no studies comparing rFVIIa with predecessor products, only with placebo or usual care. Comparisons with usual care may be particularly susceptible to bias from site-to-site variations or advances in clinical care over time. Third, we excluded articles not published in English, albeit only 2 were comparative studies with very few patients. Fourth, we used quality criteria to determine which observational studies were assessed in detail in the effectiveness review, such that others may have come to different determinations. Nonetheless, these criteria were applied systematically, and qualitative sensitivity testing found that the poor-quality studies had similar findings to their better-quality counterparts. Fifth, in 2 of the body trauma RCTs (36), patients who had been enrolled under protocols with emergency exceptions to informed consent withdrew consent. Because no information was provided on their treatment groups, we were unable to assess for differential withdrawal. Sixth, the manufacturer of rFVIIa, Novo Nordisk, played a substantial role in sponsoring, designing, directing, analyzing, and publishing much of the RCT evidence. Although this circumstance might be expected and does not equate with biased research, it does require special care in evaluating the possibility of bias. Next, we cannot exclude the possibility of selective reporting or publication bias, because the small number of available studies prevents their formal assessments (for example, by using funnel plots). Finally, we found that available studies used usual care as the comparator and relied heavily on indirect outcomes, both of which may yield more favorable findings than other design options, such as those that use an active comparator or direct outcomes.

In conclusion, off-label use of rFVIIa for ICH and cardiac surgery does not reduce mortality but does increase the risk for thromboembolism. For body trauma, there was no increased risk for thromboembolism and a reduced risk for ARDS but no difference in mortality. For the remaining indications, the available evidence was too limited to do meta-analyses. Thus, limited evidence on off-label rFVIIa use for 5 indications detects no mortality benefit but does detect an increase in thromboembolism for some indications.

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Figures

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Appendix Figure.
Summary of evidence search and selection.

CCTR = Cochrane Central Register of Controlled Trials; DARE = Database of Abstracts of Reviews of Effects; RCT = randomized, controlled trial; rFVIIa = recombinant factor VIIa.

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Figure 1.
Mortality and thomboembolic event risk differences (rFVIIa minus usual care) for indications with at least 2 comparative studies included in the effectiveness review.

Indications with 2 or more comparative studies are included in the figure: ICH (3033, 44), cardiac surgery (3435, 4548), body trauma (3637, 4951), brain trauma (38, 52), and liver transplantation (3942, 53). Each circle represents a study. Larger circles correspond to larger studies, shaded circles represent studies on treatment use of rFVIIa, and open circles represent studies on prophylactic use of rFVIIa. Intracranial hemorrhage outcomes here reflect total TE events in contrast to the arterial TE events assessed in the meta-analyses. For cardiac surgery, 3 study circles overlap at the 0 abscissa for mortality risk, and 2 similarly overlap for TE event risk. ICH = intracranial hemorrhage; rFVIIa = recombinant factor VIIa; TE = thromboembolic.

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

For ICH, all studies are RCTs (30–33) and meta-analyses are done according to dosing category (low, medium, and high). For cardiac surgery, the studies by Diprose and colleagues (34) and Gill and coworkers (35) are RCTs, whereas those by Karkouti and colleagues (45) and Gelsomino and coworkers (46) are observational studies. For body trauma, all studies are RCTs (36, 37). ICH = intracranial hemorrhage; RCT = randomized, controlled trial; RD = risk difference; rFVIIa = recombinant factor VIIa.

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

For ICH, all studies are RCTs (3033), meta-analyses are done according to dosing category (low, medium, and high), and analyses of thromboembolic events are for arterial events only. For cardiac surgery, the studies by Diprose and colleagues (34) and Gill and coworkers (35) are RCTs, whereas those by Karkouti and colleagues (45) and Gelsomino and coworkers (46) are observational studies, and the meta-analyses of thromboembolic events evaluate all events (both arterial and venous). For body trauma, all studies are RCTs (3637), and the meta-analyses of thromboembolic events evaluate all events. ICH = intracranial hemorrhage; RCT = randomized, controlled trial; RD = risk difference; rFVIIa = recombinant factor VIIa.

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Figure 4.
Harms analysis: weighted mortality and thromboembolic events in all RCTs and observational studies, by indication.

Harms analyses include patients who received recombinant factor VIIa from registries and cohorts (noncomparative observational studies) with at least 15 patients (ICH [7072], cardiac surgery [7383], body trauma [8487], brain trauma [8889], and liver transplantation [9091]), as well as patients from the treatment groups of all RCTs (3043) and comparative observational studies (4469), regardless of quality. For liver transplantation, the reported RCT rate of TE events is an underestimate, because 1 RCT (40) did not report venous events by group (treatment vs. placebo), so the events could not be tallied. For studies with overlapping data sets (e.g., the same registry patients being evaluated in a noncomparative study and a comparative observational study), the most complete data set for the outcome of interest was used. Comp Obs = comparative observational study; ICH = intracranial hemorrhage; Noncomp Obs = noncomparative observational study; RCT = randomized, controlled trial; TE = thromboembolic.

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Tables

Table Jump PlaceholderTable.  In-Depth Assessment of Studies in Effectiveness Review: Outcomes, Strength of Evidence, and Conclusions
Table Jump PlaceholderAppendix Table 1.  Mortality and Poor Functional Outcome on Modified Rankin Scale Score in Comparative Studies of rFVIIa Use in Intracranial Hemorrhage
Table Jump PlaceholderAppendix Table 2.  Thromboembolic Events (Arterial and Venous) in Comparative Studies of rFVIIa Use in Intracranial Hemorrhage
Table Jump PlaceholderAppendix Table 3.  Indirect Outcomes in Comparative Studies of rFVIIa Use in Intracranial Hemorrhage
Table Jump PlaceholderAppendix Table 4.  Mortality and Thromboembolic Events in Comparative Studies of rFVIIa Use in Cardiac Surgery
Table Jump PlaceholderAppendix Table 5.  Indirect Outcomes in Comparative Studies of rFVIIa Use in Adult Cardiac Surgery
Table Jump PlaceholderAppendix Table 6.  Mortality, Thromboembolic Events, and ARDS in Comparative Studies of rFVIIa Use in Body Trauma
Table Jump PlaceholderAppendix Table 7.  Indirect Outcomes in Comparative Studies of rFVIIa Use in Body Trauma
Table Jump PlaceholderAppendix Table 8.  Mortality, Thromboembolic Events, and Absolute Change in Hematoma Volume in Comparative Studies of rFVIIa Use in Brain Trauma
Table Jump PlaceholderAppendix Table 9.  Mortality and Thromboembolic Events in Comparative Studies of rFVIIa Use in Liver Transplantation
Table Jump PlaceholderAppendix Table 10.  Indirect Outcomes in Comparative Studies of rFVIIa Use in Liver Transplantation
Table Jump PlaceholderAppendix Table 11.  Mortality and Thromboembolic Events in RCTs on rFVIIa Use in Prostatectomy
Table Jump PlaceholderAppendix Table 12.  Indirect Outcomes in RCTs on rFVIIa Use in Prostatectomy

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Kaliciński P, Markiewicz M, Kamiński A, Laniewski P, Ismail H, Drewniak T. et al.  Single pretransplant bolus of recombinant activated factor VII ameliorates influence of risk factors for blood loss during orthotopic liver transplantation. Pediatr Transplant. 2005; 9:299-304.
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Niemann CU, Behrends M, Quan D, Eilers H, Gropper MA, Roberts JP. et al.  Recombinant factor VIIa reduces transfusion requirements in liver transplant patients with high MELD scores. Transfus Med. 2006; 16:93-100.
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De Gasperi A, Baudo F, De Carlis L.  Recombinant FVII in orthotopic liver transplantation (OLT): a preliminary single centre experience [Letter]. Intensive Care Med. 2005; 31:315-6.
PubMed
 
Sutherland CS, Hill MD, Kaufmann AM, Silvaggio JA, Demchuk AM, Sutherland GR.  Recombinant factor VIIa plus surgery for intracerebral hemorrhage. Can J Neurol Sci. 2008; 35:567-72.
PubMed
 
Nussbaum ES, Janjua TM, Defillo A, Sinner P, Zelensky A.  Perioperative use of recombinant factor VII to prevent intraoperative aneurysm rupture in high risk patients: a preliminary safety evaluation. Neurocrit Care. 2009; 10:55-60.
PubMed
 
Robinson MT, Rabinstein AA, Meschia JF, Freeman WD.  Safety of recombinant activated factor VII in patients with warfarin-associated hemorrhages of the central nervous system. Stroke. 2010; 41:1459-63.
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Tatoulis J, Theodore S, Meswani M, Wynne R, Hon-Yap C, Powar N.  Safe use of recombinant activated factor VIIa for recalcitrant postoperative haemorrhage in cardiac surgery. Interact Cardiovasc Thorac Surg. 2009; 9:459-62.
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Filsoufi F, Castillo JG, Rahmanian PB, Scurlock C, Fischer G, Adams DH.  Effective management of refractory postcardiotomy bleeding with the use of recombinant activated factor VII. Ann Thorac Surg. 2006; 82:1779-83.
PubMed
 
Gandhi MJ, Pierce RA, Zhang L, Moon MR, Despotis GJ, Moazami N.  Use of activated recombinant factor VII for severe coagulopathy post ventricular assist device or orthotopic heart transplant. J Cardiothorac Surg. 2007; 2:32.
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Hyllner M, Houltz E, Jeppsson A.  Recombinant activated factor VII in the management of life-threatening bleeding in cardiac surgery. Eur J Cardiothorac Surg. 2005; 28:254-8.
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McCall P, Story DA, Karalapillai D, Karapillai D.  Audit of factor VIIa for bleeding resistant to conventional therapy following complex cardiac surgery. Can J Anaesth. 2006; 53:926-33.
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Raivio P, Suojaranta-Ylinen R, Kuitunen AH.  Recombinant factor VIIa in the treatment of postoperative hemorrhage after cardiac surgery. Ann Thorac Surg. 2005; 80:66-71.
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Aggarwal A, Malkovska V, Catlett JP, Alcorn K.  Recombinant activated factor VII (rFVIIa) as salvage treatment for intractable hemorrhage. Thromb J. 2004; 2:9.
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Karkouti K, Beattie WS, Arellano R, Aye T, Bussieres JS, Callum JL. et al.  Comprehensive Canadian review of the off-label use of recombinant activated factor VII in cardiac surgery. Circulation. 2008; 118:331-8.
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Bruckner BA, DiBardino DJ, Ning Q, Adeboygeun A, Mahmoud K, Valdes J. et al.  High incidence of thromboembolic events in left ventricular assist device patients treated with recombinant activated factor VII. J Heart Lung Transplant. 2009; 28:785-90.
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Masud F, Bostan F, Chi E, Pass SE, Samir H, Stuebing K. et al.  Recombinant factor VIIa treatment of severe bleeding in cardiac surgery patients: a retrospective analysis of dosing, efficacy, and safety outcomes. J Cardiothorac Vasc Anesth. 2009; 23:28-33.
PubMed
 
Hsia CC, Zurawska JH, Tong MZ, Eckert K, McAlister VC, Chin-Yee IH.  Recombinant activated factor VII in the treatment of non-haemophilia patients: physician under-reporting of thromboembolic adverse events. Transfus Med. 2009; 19:43-9.
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Knudson MM, Cohen MJ, Reidy R, Jaeger S, Bacchetti P, Jin C. et al.  Trauma, transfusions, and use of recombinant factor VIIa: a multicenter case registry report of 380 patients from the Western Trauma Association. J Am Coll Surg. 2011; 212:87-95.
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Cameron P, Phillips L, Balogh Z, Joseph A, Pearce A, Parr M. et al.  The use of recombinant activated factor VII in trauma patients: experience from the Australian and New Zealand haemostasis registry. Injury. 2007; 38:1030-8.
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Martinowitz U, Michaelson M, Israeli Multidisciplinary rFVIIa Task Force.  Guidelines for the use of recombinant activated factor VII (rFVIIa) in uncontrolled bleeding: a report by the Israeli Multidisciplinary rFVIIa Task Force. J Thromb Haemost. 2005; 3:640-8.
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McQuay N Jr, Cipolla J, Franges EZ, Thompson GE.  The use of recombinant activated factor VIIa in coagulopathic traumatic brain injuries requiring emergent craniotomy: is it beneficial? J Neurosurg. 2009; 111:666-71.
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Jarosz K, Czupryńska M, Andrzejewska J, Wasilewicz MP, Post M, Lubikowski J. et al.  Administration of a recombinant factor Vlla in patients undergoing liver transplantation for fulminant hepatic failure. Transplant Proc. 2009; 41:3088-90.
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Friedrich JO.  Recombinant activated factor VII for acute intracerebral hemorrhage [Letter]. N Engl J Med. 2005; 352:2133-4.
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Hsia CC, Chin-Yee IH, McAlister VC.  Use of recombinant activated factor VII in patients without hemophilia: a meta-analysis of randomized control trials. Ann Surg. 2008; 248:61-8.
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Pohar S, Tsakonas E, Murphy G, Anderson D, Carney D, Moltzan C. et al.  Recombinant activated factor VII in treatment of hemorrhage unrelated to hemophilia: a systematic review and economic evaluation. Technology report number 118. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2009.
 
Birchall J, Stanworth SJ, Duffy MR, Doree CJ, Hyde C.  Evidence for the use of recombinant factor VIIa in the prevention and treatment of bleeding in patients without hemophilia. Transfus Med Rev. 2008; 22:177-87.
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Johansson PI.  Off-label use of recombinant factor VIIa for treatment of haemorrhage: results from randomized clinical trials. Vox Sang. 2008; 95:1-7.
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Duchesne JC, Mathew KA, Marr AB, Pinsky MR, Barbeau JM, McSwain NE.  Current evidence based guidelines for factor VIIa use in trauma: the good, the bad, and the ugly. Am Surg. 2008; 74:1159-65.
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Logan et al. and Yank et al. articles do not put rFVIIa use into proper context
Posted on April 19, 2011
Anne Phillips
Novo Nordisk Inc.
Conflict of Interest: None Declared

In the April 19th issue of Annals, Logan et al. and Yank et al. present a summary of their AHRQ-sponsored assessment [1]. Novo Nordisk is concerned that these articles do not put rFVIIa use into proper context. The majority of rFVIIa use is in hemophilia with inhibitors in the outpatient setting.

In 1972, Ulla Hedner discovered that coagulation factor VII was able to bypass factor VIII/IX-mediated clotting in patients with hemophilia complicated by alloantibodies. Due to the limited availability of plasma FVII and the risk of transmitting infectious agents Novo Nordisk agreed to develop a recombinant FVIIa in 1985. After the conduct of several successful clinical trials, rFVIIa was approved by EMA in 1996 and the FDA in 1999 for use in hemophilia patients with inhibitors, and subsequently in acquired hemophilia, congenital factor VII deficiency, and to prevent bleeding during surgery in those patients.

The use of rFVIIa outside of hemophilia is relatively recent. In 1999, Israeli hematologists, faced with a 19-year-old soldier with a gunshot wound to the vena cava and coagulopathy refractory to treatment and surgery, successfully used rFVIIa to sufficiently correct the coagulopathy which allowed for surgical repair [2].

Logan et al. reviewed the analysis of the PREMIER database of selected hospitals to assess the percentage of off-label use of rFVIIa without mentioning a key fact noted in the full AHRQ report. "The majority of use of rFVIIa occurs in the outpatient setting, and the majority of outpatient use is for on-label indications related to hemophilia."[1] Thus, their analysis describes only a small portion of overall rFVIIa use.

Yank et al. reviewed studies reported in the literature and data provided to AHRQ by Novo Nordisk to assess the benefits and risks of rFVIIa in critical bleeding. Their conclusions on rFVIIa-associated mortality and safety do not differ from the recent Cochrane review, other meta-analyses, or the analysis from the Novo Nordisk safety database published by Levi et al. last year [3,4,5].

Novo Nordisk has proactively modified the rFVIIa package insert several times in the past years in collaboration with regulatory agencies to warn about the potential risk of arterial thromboembolic events outside of labeled indications and does not promote the use of rFVIIa outside of approved indications.

NovoSeven RT has been used for more than a decade across the world to improve the lives of patients and to treat bleeding episodes and prevent bleeding during surgery in patients with hemophilia with inhibitors, acquired hemophilia, and congenital factor VII deficiency.

Anne Phillips, MD Vice President, Clinical, Medical and Regulatory Affairs, Novo Nordisk Inc. Princeton, New Jersey

References:

1. Yank V, Tuohy CV, Logan AC, Bravata DM, Staudenmayer K, Eisenhut R, Sundaram V, McMahon D, Stave CD, Zehnder JL, Olkin I, McDonald KM, Owens DK, Stafford RS. Comparative Effectiveness of Recombinant Factor VIIa for Off-Label Indications vs. Usual Care. Comparative Effectiveness Review No. 21. (Prepared by Stanford-UCSF Evidence-based Practice Center under Contract No. #290-02-0017) Rockville, MD: Agency for Healthcare Research and Quality. May 2010. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

2. Kenet G, Walden R, Eldad A, and Martinowitz U. Treatment of traumatic bleeding with recombinant factor VIIa. Lancet 1999. 354(9193):1879.

3. Lin Y, Stanworth S, Birchall J, Doree C, Hyde C. Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database Syst Rev. Available online 2011 Feb 16.

4. Hsia CC, Chin-Yee IH, McAlister MB. Use of Recombinant Activated Factor VII in Patients without Hemophilia: A Meta-Analysis of Randomized Control Trials. Ann Surg 2008:248:61-68.

5. Levi M, Levy JH, Andersen HF, Truloff D. Safety of Recombinant Activated Factor VII in Randomized Clinical Trials. N Engl J Med 2010;363: 1791-800.

Conflict of Interest:

Dr. Anne Phillips is an employee of Novo Nordisk Inc. (Princeton, NJ).

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