Fibrinogen Concentrate vs Cryoprecipitate in Pseudomyxoma Peritonei Surgery: Interim Results from a Prospective, Randomized, Controlled Phase 2 Study

Scientific Research Question: Maintaining adequate plasma fibrinogen concentration during cytoreductive surgery may help control hemostasis. We present data from the planned interim analysis of FORMA-05, which aims to compare hemostatic efficacy and safety of cryoprecipitate with a new highly purified, double virus-inactivated human fibrinogen concentrate.

Methodology: FORMA-05 is a prospective, single center, randomized, controlled phase 2 study in patients with acquired fibrinogen deficiency undergoing cytoreductive surgery for Pseudomyxoma peritonei (PMP). Patients who required intraoperative fibrinogen supplementation (predicted intraoperative blood loss ≥2 L without fibrinogen supplementation) were randomized to preemptively receive fibrinogen concentrate (4 g) or cryoprecipitate (2 pools, 5 units each). The primary endpoint was a composite of intraoperative efficacy (assessed by the surgeon and anesthesiologist at the end of surgery) and postoperative efficacy (assessed by the hematologist 24 hour after the end of surgery), graded using an objective four-point scale and adjudicated by an Independent Data Monitoring and Endpoint Adjudication Committee (IDMEAC).

Results: The per-protocol set included 24 patients (fibrinogen concentrate, n = 11; cryoprecipitate, n = 13). The mean total intraoperative dose of fibrinogen was 6.4 g and the estimated mean dose of cryoprecipitate was 7.7–8.9 g (allowing for variation between batches). Intraoperative hemostatic efficacy was judged as excellent or good for 90.0% and 76.9% of patients who received fibrinogen concentrate and cryoprecipitate, respectively (IDMEAC: 90.0% vs 61.6%). Postoperative hemostatic efficacy was deemed to be excellent for all 24 patients. Preemptive infusion was initiated 0.5 hour earlier with fibrinogen concentrate than cryoprecipitate due to faster product availability. Overall, intraoperative fibrinogen concentrate administration led to a mean increase of 3.1 mm in FIBTEM A20 vs 0.6 mm with cryoprecipitate (p < 0.01). A significantly higher mean increase in fibrinogen concentration was obtained with administration of fibrinogen concentrate than with cryoprecipitate (0.7 g/L vs 0.3 g/L; p = 0.01).

Intraoperative blood loss was comparable between groups (mean difference, 138 mL: 95% CI: -508, 232; n.s.). There were 2 serious adverse events (AEs) in the fibrinogen concentrate group and 9 in the cryoprecipitate group,including 4 thromboembolic events (TEEs) (2 deep vein thromboses and 2 pulmonary embolisms). No AEs were assessed as related to study drug administration.

A total of 48 patients were enrolled by study completion and safety and efficacy results are in line with the interim analysis. Full study results are expected late 2018.

Conclusions: In this interim analysis, fibrinogen concentrate was at least as efficacious as cryoprecipitate with no related AEs and no TEEs in the treatment of bleeding related to acquired fibrinogen deficiency in patients undergoing cytoreductive surgery for PMP.