Efficacy of prothrombin complex concentrate in the management of oral factor Xa inhibitors associated major bleed assessed by ISTH and ANNEXA-4 criteria

Abstract

Direct oral anticoagulants (DOACs) are increasingly used for stroke prevention in atrial fibrillation and treatment and prevention of venous thromboembolism. They are also associated with bleeding risk. Existing literature suggests that prothrombin complex concentrate (PCC) administration may help control bleeding due to factor Xa inhibitors (FXaI). To determine the hemostatic efficacy of PCC in patients with major bleeding due to FXaI, we performed a retrospective chart review of 50 patients who presented with FXaI associated major bleeding that required urgent hemostatic management. Hemostatic assessment was performed using ISTH and ANNEXA-4 criteria. Twenty patients presented with intracranial hemorrhage (ICH), 20 had gastrointestinal bleeding, 3 had visceral bleeding, 3 had genitourinary bleeding, and 4 had miscellaneous types of bleeding. Fifty-six percent (28/50) had effective hemostasis using ISTH criteria and 84% (42/50) achieved effective hemostasis by ANNEXA-4 criteria. Hemostatic efficacy was similar by both tools for ICH (75% each). However, there was a major difference between ISTH and ANNEXA-4 hemostatic efficacy assessments for GI bleeding (45% and 95%, respectively). When comparing rivaroxaban and apixaban, there was no significant difference in effective hemostasis using either criteria, time to hemostasis, thromboembolic events, or patient mortality. Five (10%) patients had thromboembolic events within seven days of PCC administration, and the 30-day mortality rate was 14% (7/50). Our study shows similar efficacy, thromboembolic events, and mortality associated with PCC compared to andexanet alfa using ANNEXA-4 criteria, suggesting that PCC may be a viable alternative.

Evaluation of Direct Oral Anticoagulant Reversal Agents in Intracranial Hemorrhage

“…Several other smaller studies have shown the use of 4F-PCCs as a viable reversal option for DOAC-related ICH for anticoagulation reversal (reversal rates, 54.5%-94.7%) and safety (mortality rates, 4.7%-63.6%; thrombotic event rate, 0%-17.2%). 8 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 Albeit with significant heterogeneity, our meta-analysis found a combined proportion of anticoagulation reversed of 77%, a mortality rate of 26%, and a thromboembolic event rate of 8% ( Figures 1 - 3 ).…”

“…Thirty-six studies were included in the meta-analysis (eAppendix 1 in the Supplement ). Twenty-two studies with 967 participants evaluated 4F-PCC for reversal 8 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ; 17 studies with 525 participants evaluated AA 13 , 35 , 36 , 37 , 39 , 40 , 41 , 42 , 44 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ; and 5 studies with 340 participants evaluated idarucizumab, 12 , 53 , 54 , 55 , 56 consisting of a total of 1832 patients with ICH while receiving treatment with a DOAC. Eight studies had data on more than 1 agent.…”

“…Thirty-six studies were included in the meta-analysis (eAppendix 1 in the Supplement). Twenty-two studies with 967 participants evaluated 4F-PCC for reversal; 17 studies with 525 participants evaluated AA; and 5 studies with 340 participants evaluated idarucizumab, consisting of a total of 1832 patients with ICH while receiving treatment with a DOAC. Eight studies had data on more than 1 agent .…”

Direct oral anticoagulants in pediatric venous thromboembolism: Review of approved products rivaroxaban and dabigatran

“…Andexanet alfa is an inactive recombinant factor Xa, and in the ANNEX-4 study (27), 80% of patients with acute major bleeding (intracranial or gastrointestinal) secondary to an oral DFXaI, achieved improved hemostatic function with administration of andexanet alfa. The reversal agent is expensive and not readily available in many institutions, with prothrombin complex concentrates (PCCs) being an alternative therapy (28).…”

“…Andexanet alfa is an inactive recombinant factor Xa, and in the ANNEX-4 study ( 27 ), 80% of patients with acute major bleeding (intracranial or gastrointestinal) secondary to an oral DFXaI, achieved improved hemostatic function with administration of andexanet alfa. The reversal agent is expensive and not readily available in many institutions, with prothrombin complex concentrates (PCCs) being an alternative therapy ( 28 ). As there are no current pediatric specific data on its use, a recent survey of pediatric hematologists found a 44% preference for the use of andexanet alfa in pediatric patients requiring reversal for acute life threatening bleed due to FXaI, with 55% choosing PCCs ( 29 ).…”