SAFETY AND EFFECTIVENESS OF ACTIVATED PROTHROMBIN COMPLEX CONCENTRATE (APCC) MONOTHERAPY IN PATIENTS WITH HEMOPHILIA AND INHIBITORS (PWHI) UNDERGOING SURGERY: A SYSTEMATIC REVIEW AND META-ANALYSIS

Introduction: Control of hemostasis during and after surgical procedures in PwHI is challenging. aPCC (Feiba®, Baxalta Inc, a Takeda company, Lexington, MA, USA), a bypassing agent, is indicated for patients with congenital hemophilia A or B with inhibitors for on-demand, prophylaxis and perioperative management, and for acquired hemophilia patients. We present a systematic literature review of studies reporting aPCC safety and a meta-analysis of the hemostatic effectiveness of aPCC monotherapy during major and minor surgical procedures in PwHI. Methods: This systematic review and meta-analysis was carried out in MedLine through Pubmed from January 1, 1980 (aPCC inception) to June 30, 2018. Prospective, retrospective, randomized and non-randomized studies that reported the safety and hemostatic effectiveness of aPCC monotherapy in PwHI during surgery were eligible. Studies investigating concomitant/sequential infusion of aPCC with rFVIIa, tranexamic acid or emicizumab were excluded. Safety outcomes included serious adverse events (SAEs), including thromboembolic event (TEE), thrombotic microangiopathy (TMA), and other AEs associated with aPCC monotherapy. The hemostatic effectiveness was assessed intraoperatively by the surgeon and late postoperatively by the hematologist and rated as “excellent, good, fair or poor”. Results: Of 645 publications describing aPCC as monotherapy in PwHI, 14 publications (including 158 patients) reported aPCC monotherapy in a surgical setting (100 major and 162 minor surgeries). TEE occurrence was reported in 4 major surgeries in 4 patients. One SAE of a clot in an arteriovenous fistula (possibly-related to aPCC) was reported. No reports of TMAs were identified in publications of studies that used aPCC as monotherapy. The proportion (95% confidence interval, CI) of major procedures in which hemostatic effectiveness was rated as excellent/good was 0.91 [(0.83-0.99); p=0.04 for heterogeneity] and for minor procedures this was 0.98 [(0.95-1.00); p=0.86 for heterogeneity]. Discussion/Conclusion: In this analysis of published studies involving patients treated with aPCC monotherapy in a surgical setting, a low rate of TEE occurrence and no TMAs were reported, while the hemostatic effectiveness of aPCC monotherapy was rated as excellent/good in >90% of both minor and major surgical procedures.