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; Randall S. Stafford, MD, PhD
Yank V, Tuohy CV, Logan AC, Bravata DM, Staudenmayer K, Eisenhut R, et al. Systematic Review: Benefits and Harms of In-Hospital Use of Recombinant Factor VIIa for Off-Label Indications. Ann Intern Med. 2011;154:529-540. doi: 10.7326/0003-4819-154-8-201104190-00004
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Published: Ann Intern Med. 2011;154(8):529-540.
Recombinant factor VIIa (rFVIIa), a hemostatic agent approved for hemophilia, is increasingly used for off-label indications.
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.
Ten databases (including PubMed, EMBASE, and the Cochrane Library) queried from inception through December 2010. Articles published in English were analyzed.
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.
Two reviewers independently assessed study characteristics and rated study quality and indication-wide strength of evidence.
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.
The amount and strength of evidence were low for most outcomes and indications. Publication bias could not be excluded.
Limited available evidence for 5 off-label indications suggests no mortality reduction with rFVIIa use. For some indications, it increases thromboembolism.
Agency for Healthcare Research and Quality.
CCTR = Cochrane Central Register of Controlled Trials; DARE = Database of Abstracts of Reviews of Effects; RCT = randomized, controlled trial; rFVIIa = recombinant factor VIIa.
Indications with 2 or more comparative studies are included in the figure: ICH (30–33, 44), cardiac surgery (34, 35, 45–48), body trauma (36, 37, 49–51), brain trauma (38, 52), and liver transplantation (39–42, 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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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.
For ICH, all studies are RCTs (30–33), 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 (36, 37), and the meta-analyses of thromboembolic events evaluate all events. ICH = intracranial hemorrhage; RCT = randomized, controlled trial; RD = risk difference; rFVIIa = recombinant factor VIIa.
Harms analyses include patients who received recombinant factor VIIa from registries and cohorts (noncomparative observational studies) with at least 15 patients (ICH [70–72], cardiac surgery [73–83], body trauma [84–87], brain trauma [88, 89], and liver transplantation [90, 91]), as well as patients from the treatment groups of all RCTs (30–43) and comparative observational studies (44–69), 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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Novo Nordisk Inc.
April 19, 2011
Logan et al. and Yank et al. articles do not put rFVIIa use into proper context
In the April 19th issue of Annals, Logan et al. and Yank et al. present a summary of their AHRQ-sponsored assessment . 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 .
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." 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
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.
Dr. Anne Phillips is an employee of Novo Nordisk Inc. (Princeton, NJ).
Cardiology, Emergency Medicine, Hospital Medicine, Neurology.
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