Systematic review: benefits and harms of in-hospital use of recombinant factor VIIa for off-label indications

Abstract

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.

Conflict of interest statement

Potential Conflicts of Interest

Dr. Stafford reports a consulting relationship with Mylan Pharmaceuticals. Over the past five years, he reports past honoraria from Bayer, and past grant funding from Procter and Gamble, Bayer, Merck and Company, SmithKlineGlaxo, Toyo Shinyaku, and Wako Chemical USA. Dr. Owens has a consulting relationship with Sanofi-Aventis. Drs. Yank, Logan, Bravata, Staudenmayer, McMahon, and Olkin, Mr. Tuohy, and Ms. Eisenhut, Ms. Sundaram, and Ms. McDonald have no disclosures.

Figures

Figure 1

Literature search and study inclusion or exclusion

Figure 2

Mortality and thomboembolic event risk differences (rFVIIa minus usual care) for indications with at least two comparative studies included in the effectiveness review Figure includes indications with two or more comparative studies included in the effectiveness review: ICH (–33, 44)), cardiac surgery (–, –48), body trauma (–, –51), brain trauma (38, 52), and liver transplantation (–42, 53). Each circle represents a study; larger circles correspond to larger studies; shaded circles represent studies on treatment use of rFVIIa, and white circles represent studies on prophylactic use of rFVIIa. ICH outcomes here reflect total thromboembolic events, as compared to the arterial thromboembolic events assessed in meta-analyses. For cardiac surgery, there are three study circles that overlay each other at the zero abscissa for mortality risk and there are two that similarly overlay each other for thromboembolic risk. TE=thromboembolic.

Figure 3

Meta-analysis of off-label rFVIIa use for ICH and adult cardiac surgery in RCTs and good quality observational studies For ICH, all studies are RCTs (–33), meta-analyses are performed 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 (34) and Gill (35) are RCTs, while those by Karkouti (45) and Gelsomino (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 (–37), and the meta-analyses of thromboembolic events evaluate all events.

Figure 3

Meta-analysis of off-label rFVIIa use for ICH and adult cardiac surgery in RCTs and good quality observational studies For ICH, all studies are RCTs (–33), meta-analyses are performed 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 (34) and Gill (35) are RCTs, while those by Karkouti (45) and Gelsomino (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 (–37), and the meta-analyses of thromboembolic events evaluate all events.

Figure 4

Harms analysis: weighted mortality and thromboembolic events by indication in all RCTs and observational studies Harms analyses include rFVIIa patients from registries and cohorts (non-comparative observational studies (Non Comp Obs)) with at least 15 patients comparative (ICH (–72), cardiac surgery (–83), body trauma (–87), brain trauma (–89), and liver transplantation (–91), as well as patients from the treatment arms of all RCTS (–43) and comparative observational studies (Comp Obs) (–69) regardless of quality. For liver transplantation, the reported RCT rate of thromboembolism is an underestimate, because one RCT (40) did not report venous events by arm (treatment versus placebo) and so the events could not be tallied. For studies with overlapping data sets (e.g., the same registry patients being evaluated in a non-comparative study and a comparative observational study), we used the most complete data set for the outcome of interest.