The role of recombinant factor VIIa in on-pump cardiac surgery: Proceedings of the Canadian Consensus Conference

Abstract

Purpose: Recombinant activated factor VII (rFVIIa) is currently not approved by Health Canada or the Food and Drug Administration for treating excessive blood loss in nonhemophiliac patients undergoing on-pump cardiac surgery, but is increasingly being used "off-label" for this indication. A Canadian Consensus Conference was convened to generate recommendations for rFVIIa use in on-pump cardiac surgery. Methods: The panel undertook a literature review of the use of rFVIIa in both cardiac and non-cardiac surgery. Appropriateness, timing, and dosage considerations were addressed for three cardiac surgery indications: prophylactic, routine, and rescue uses. Recommendations were based on evidence from the literature and derived by consensus following recognized grading procedures. Results: The panel recommended against prophylactic or routine use of rFVIIa, as there is no evidence at this time that the benefits of rFVIIa outweigh its potential risks compared with standard hemostatic therapies. On the other hand, the panel made a weak recommendation (grade 2C) for the use of rFVIIa (one to two doses of 35-70 µg·kg -1 ) as rescue therapy for blood loss that is refractory to standard hemostatic therapies, despite the lack of randomized controlled trial data for this indication. Conclusions: In cardiac surgery, the risks and benefits of rFVIIa are unclear, but current evidence suggests that its benefits may outweigh its risks for rescue therapy in selected patients. Methodologically rigorous studies are needed to clarify its riskbenefit profile in cardiac surgery patients. 200 Elizabeth Street, Toronto, Ontario M5G 2C4,; E-mail: keyvan.karkouti@uhn.on.ca Disclosure statement: Novo Nordisk (Mississauga, Ontario, Canada), the makers of rFVIIa, funded this project through an unrestricted educational grant. Novo Nordisk was not involved in the selection of the members of the consensus panel, nor were they involved in the panel's review process, deliberations, conclusions, or manuscript preparation. The panel's chair selected the panel members, with the objective of achieving relevant multi-disciplinary expertise (i.e., anesthesiology, cardiac surgery, hematology, intensive care, and clinical epidemiology). The manuscript was primarily written by the panel chair (Keyvan Karkouti) and was approved by all of the panel members. All of the authors received an honorarium for attending the consensus conference.

Monitoring Recombinant Factor VIIa Treatment: Efficacy Depends on High Levels of Fibrinogen in a Model of Severe Dilutional Coagulopathy

“…However, in patients experiencing refractory postoperative hemorrhage, the use of rFVIIa seems promising and relatively safe although definitive evidence from randomized controlled trials is lacking. 30,31 Doses of rFVIIa ranging from 20-200 μg/kg have been given with varying success and 90-120 μg/kg of rFVIIa is generally considered the recommended initial dose. 3,4,32 Our results in severe hemodilution suggest that half of the 12 recommended dose (~50 μg/kg, final concentration of 0.7 μg/ml) has similar effect as compared to the full dose.…”

Comprehensive Canadian Review of the Off-Label Use of Recombinant Activated Factor VII in Cardiac Surgery

“…Whether rFVIIa is safe and effective outside these approved indications in adult cardiac surgery has not yet been elucidated by largescale, randomized, placebo-controlled clinical trials; current best evidence is limited primarily to case-control studies. 2 Nevertheless, owing to the heavy burden of excessive blood loss, current recommendations are that it is reasonable to consider rFVIIa therapy in cases of excessive blood loss that is unresponsive to standard interventions, 3,4 and as a result the drug is being increasingly used in this setting. 5 Given the unresolved safety and effectiveness issues, however, some have questioned the appropriateness of the off-label use of the drug in cardiac surgery and other settings.…”

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

“…For brain trauma, a recent Cochrane review by Perel and colleagues identified few studies and no mortality benefit(105). Other reviews were more supportive of rFVIIa, describing it as a “promising” therapy (106) or one that might reasonably be used as rescue therapy(107–108), but did not perform meta-analyses. Specific to harms analyses, O’Connell and colleagues evaluated data from the FDA’s Adverse Event Reporting System to document serious thromboembolic events following off-label rFVIIa use(1).…”