Evaluation of 4-Factor Prothrombin Complex Concentrates Dosing For Factor Xa Inhibitor Reversal Cody Craven, PharmD PGY-1 Pharmacy Resident SSM Health Saint Louis University Hospital James Braun, PharmD, BCCCP Robert Sbertoli, PharmD, BCCCP Joanna Ramiro, MD
Background • Direct acting oral anticoagulants (DOACs) – Factor Xa inhibitors (FXaI) – Direct thrombin inhibitors • Indications – Atrial fibrillation – VTE prophylaxis – VTE treatment • Landmark trials • Increased risk of bleeding • 4-factor prothrombin complex concentrates (4F- PCC) as a possible reversal agent Granger CB, et al. N Engl J Med . 2011;365:981 – 992. Patel MR, et al. N Engl J Med . 2011;365:883 – 891. 2 Agnelli G, et al. N Engl J Med . 2013;369:799 – 808. Bauersachs R, et al. N Engl J Med . 2010;363:2499 – 2510.
Evidence Progression • Small studies in healthy volunteers • Used laboratory parameters to assess bleeding reversal Randomized • Complete reversal at 50 units/kg Trials • NCS 2016, ACC 2017, ASH 2018 guidelines recommend 4F-PCC for reversal of FXaI-associated bleeding • Recommended dose: 50 units/kg Guidelines • Patients with FXaI-associated major bleeds • Study doses approximated 25 units/kg Observations • 4F-PCC appears to be safe and effective • FDA approved in May 2018 • ANNEXA-4: no comparison to standard of care/restrictive exclusion criteria Andexanet • High rates of thromboembolic complications Alfa Levi M, et al. J Thromb Haemost. 2014;12:1428 – 1436. Frontera JA, et al. Neurocrit Care . 2015;24:6 – 46. Eerenberg ES, et al. Circulation . 2011;124:1573 – 1579. Schulman S, et al. J Thromb Haemost . 2018;118:842 – 851. Cheung YW, et al. J Thromb Haemost . 2015;13:1799 – 1805. Majeed A, et al. Blood . 2017;130:1706 – 1712. 3 Zahir H, et al. Circulation . 2015;131:82 – 90. Grandhi R, et al. World Neurosurg . 2015;84:1956 – 1961. Tomaselli GF, et al. J Am Coll Cardiol . 2017;70:3042 – 3067. Connolly SJ, et al. N Engl J Med . 2019;380:1326 – 1335.
SLUH Approach • Anticoagulation reversal policy – Established in 2014 – Recommended 4F-PCC dose = 50 units/kg for FXaI-associated major bleeding – Mirrors guideline recommendations • Andexanet alfa not on current formulary 4
Study Design • Purpose: To evaluate the efficacy and safety of administering 4F-PCC at a dose of 50 units/kg for the reversal of FXaI-associated bleeding at SSM Health Saint Louis University Hospital • Retrospective chart review • Approved by SLU IRB 356-bed Primary Level I academic stroke trauma center center 5
Selection Patients Inclusion Criteria Exclusion Criteria • Age 18 years or older • Placed on comfort care measures within • Received 4F-PCC for 48 hours of admission reversal of FXaI- associated bleed • Acute coronary syndrome or ischemic stroke within the past 30 days 6
Outcomes • Efficacy • Achievement of excellent/good hemostasis Primary • Safety • Thromboembolic events at 30 days • All-cause mortality • Time from 4F-PCC order to admin Secondary • Length of stay in ICU • Length of stay in hospital • Modified Rankin Score at discharge 7
Modified Sarode Criteria Bleed Type Excellent (effective) Good (effective) Poor/none (not effective) Intracerebral ≤20% increase in >20% but ≤35% increase in >35% increase in hematoma hemorrhage hematoma volume hematoma volume volume compared to compared to baseline on compared to baseline on baseline on follow-up follow-up imaging follow-up imaging imaging Subarachnoid ≤20% increase in >20% but ≤35% increase in >35% increase in maximum bleed maximum thickness using maximum thickness using thickness using the densest the densest area the densest area compared area compared to baseline compared to baseline on to baseline on follow-up on follow-up imaging follow-up imaging imaging Subdural ≤20% increase in >20% but ≤35% increase in >35% increase in maximum hematoma maximum thickness maximum thickness thickness compared to compared to baseline on compared to baseline on baseline on follow-up follow-up imaging follow-up imaging imaging 8
Statistical Approach • Hypothesis: – In patients with FXaI-associated bleeds, 4F-PCC at a dose of 50 units/kg will demonstrate effective hemostasis with low rates of thromboembolism. • Categorical data – Fisher’s exact test • Continuous data – Expressed as medians and ranges – Mann-Whitney U-test • Binary logistic regression • All analysis completed via SPSS software 9
Study Population Screened: 41 patients Excluded: 11 patients 9 - Comfort Care at 48 hrs 1 - 4F-PCC never administered 1 - Andexanet alfa at OSH Final Analysis: 30 patients Apixaban: 17 Rivaroxaban: 13 10
Baseline Characteristics Baseline Characteristics Variable n = 30 Age, years, median (range) 75.5 (31-94) Sex, male, n (%) 19 (63.3) Weight, kg, median (range) 82.8 (51.3-129.3) Apixaban, n (%) 17 (56.7) Rivaroxaban, n (%) 13 (43.3) Time Since Last Dose Reported, n (%) Yes 1 (3.3) No 29 (96.7) Indication, n (%) Atrial Fibrillation 24 (80.0) VTE 4 (13.3) VTE Prophylaxis 1 (3.3) Concomitant Medications, n (%) Antiplatelets 16 (53.3) NSAIDs 4 (13.3) 11
Characteristics of Bleed Baseline Characteristics Variable n = 30 Bleed Location, n (%) ICH 22 (73.3) SAH 7 (23.3) IVH 2 (6.7) IPH 10 (33.3) SDH 3 (10.0) Gastrointestinal 3 (10.0) Other 5 (16.7) ICH Score, median (range) 2 (0-4) 0, n (%) 1 (3.3) 1 3 (10) 2 5 (16.7) 3 1 (3.3) 4 1 (3.3) Admission GCS, median (range) 14 (3-15) 12
Characteristics of Bleed Baseline Characteristics Variable n = 30 Trauma, n (%) 13 (43.3) Surgery, n (%) 12 (40.0) Craniotomy - 2 (6.6) 2 (6.6) Exploratory laparotomy with colonic resection 2 (6.6) Decompressive craniectomy 1 (3.3) Burr hole hematoma evacuation 1 (3.3) Aneurysm coiling embolization 1 (3.3) Epidural hematoma evacuation 1 (3.3) Colonoscopy 1 (3.3) Axillary thrombectomy 1 (3.3) Above knee amputation 1 (3.3) Pericardiocentesis 1 (3.3) 13
Reversal Characteristics Bleed Reversal Characteristics 4F-PCC Dose, units, median (range) 3935 (2052-5130) 4F-PCC Dose, units/kg, median (range) 49.0 (25.1-52.1) 4F-PCC Re-dose, n (%) 0 (0.0) 4F-PCC Order to Admin Time, hrs, 0.9 (0.4-2.3) median (range) Blood Products, n (%) PRBCs 9 (30.0) FFP 8 (26.7) Platelets 6 (20.0) 14
Patient Outcomes Primary Outcomes Hemostatic Efficacy, n (%) Excellent/good 24 (80.0) Excellent 22 (73.3) Good 2 (6.67) Poor/none 6 (20.0) Thromboembolic Event, n (%) 1 (3.3) Secondary Outcomes Death, n (%) 5 (16.7) Modified Rankin at Discharge, median (range) 4 (0-6) LOS Hospital, days, median (range) 7.1 (0.2-34.9) LOS ICU, days, median (range) 2.9 (0.6-27.0) Time to Restarting Anticoagulation, days, median 14.4 (2-369) (range) 15
Discussion Korobey Panos et al. This Study et al. Excellent/good: Excellent/good: Excellent/good: 81.8% 88% 80.0% Thrombotic Thrombotic Thrombotic Events: 3.8% Events: 11.9% Events: 3.3% Mortality: Mortality: Mortality: 19.0% 10.2% 16.7% Panos, et al. Neurocrit Care . 2020. 16 Korobey, et al. Circulation 2020.
Discussion Lack of ANNEXA-4 This Study control High group Excellent/ thrombotic good 82.0% 80.0% potential Hemostasis Thrombotic Restrictive 10% 3.3% Events exclusion criteria Mortality 14% 16.7% Key Exclusion Criteria • ICH with GCS < 7 • Hematoma volume > 60 mL • Expected survival < 1 month • Planned surgery within 12 hours ANNEXA-4 17 Connolly SJ, et al. N Engl J Med . 2019;380:1326 – 1335.
Strengths and Limitations Strengths • Assessed efficacy using ANNEXA-4 hemostasis definitions • Minimal exclusion criteria • Dosing strategy mirrored guideline recommendations • Imaging reviewed by board-certified neurointensivist Limitations • Lack of comparator • Small sample size • Did not evaluate blood pressure control • Inconsistent documentation of blood products administered • Time since last dose of FXaI not readily available 18
Conclusions 4F-PCC 50 units/kg is effective and safe for the reversal of FXaI-associated major bleeding 50 units/kg dose associated with low rates of thromboembolism Findings demonstrate 4F-PCC as a viable treatment option for reversal of FXaI-associated bleeding RCT needed comparing 4F-PCC to andexanet alfa 19
Evaluation of 4-Factor Prothrombin Complex Concentrates Dosing For Factor Xa Inhibitor Reversal Cody Craven, PharmD PGY-1 Pharmacy Resident SSM Health Saint Louis University Hospital James Braun, PharmD, BCCCP Robert Sbertoli, PharmD, BCCCP Joanna Ramiro, MD
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