Abstract TP328: Ischemic Stroke Following Prothrombin Complex Concentrates Administration for Intracerebral Hemorrhage

Intro: There have been case reports of ischemic infarcts after treatment with prothrombotics for anticoagulation reversal following spontaneous intracerebral hemorrhage (ICH), though there have been no systematic studies evaluating MRI infarction following prothrombin complex concentrate (PCC) or factor eight inhibitor bypassing activity (FEIBA) administration. We evaluated the prevalence of ischemic infarcts on diffusion-weighted imaging (DWI) in ICH patients who received prothrombotics compared to those who did not. Methods: We performed a retrospective review of patients admitted with ICH between January 2013 and April 2016 in whom MRI brain with DWI imaging was performed within 2 weeks of admission and prior to digital subtraction angiography. PCC (4-factor Kcentra, weight, and INR based dosing) was administered to patients on warfarin at the time of ictus with a INR≥1.4 and FEIBA (50 u/kg) was given to patients exposed to an oral Factor Xa inhibitor or direct thrombin inhibitor if ICH occurred within 3-5 half lives of the last dose. Acute ischemia was defined as DWI hyperintensity with corresponding apparent diffusion coefficient hypointensity. Perihematoma lesions, and procedure-related infarctions were excluded from analysis. Groups were compared using chi-square and Wilcoxon Rank Sum tests. Results: A total of 254 patients were enrolled. Of these, 41 (16%) received either 4-factor PCC (n=33) or FEIBA (n=8). Comparing those who received prothrombotics to those who did not, there was no difference in age (median 68 with prothrombotics and without; p=0.724), sex (44% female in both groups; p=0.977), initial NIH Stroke Scale (median 6 versus 8, p=0.838), or hematoma volume (median 15ml versus 10ml; p=0.207). Patients who received prothrombotics were more likely to have lobar ICH than deep ICH (71% versus 47%; p=0.005). DWI infarctions were found in 16% of patients who receive PCC or FEIBA compared with 22% who did not (p=0.404). Conclusions: Our data suggests prothrombotics do not increase the risk of acute ischemic infarcts within two weeks of administration.

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Hematoma Expansion and Clinical Outcomes in Patients With Factor-Xa Inhibitor–Related Atraumatic Intracerebral Hemorrhage Treated Within the ANNEXA-4 Trial Versus Real-World Usual Care

Stroke ◽

10.1161/strokeaha.121.034572 ◽

2021 ◽

Author(s):

Hagen B. Huttner ◽

Stefan T. Gerner ◽

Joji B. Kuramatsu ◽

Stuart J. Connolly ◽

Jan Beyer-Westendorf ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Hospital Mortality ◽

Usual Care ◽

Clinical Outcomes ◽

Factor Xa ◽

Hematoma Expansion ◽

Factor Xa Inhibitor ◽

Hematoma Volume ◽

Prothrombin Complex Concentrates ◽

Andexanet Alfa

Background and Purpose: It is unestablished whether andexanet alfa, compared with guideline-based usual care including prothrombin complex concentrates, is associated with reduced hematoma expansion (HE) and mortality in patients with factor-Xa inhibitor–related intracerebral hemorrhage (ICH). We compared the occurrence of HE and clinical outcomes in patients treated either with andexanet alfa or with usual care during the acute phase of factor-Xa inhibitor–related ICH. Methods: Data were extracted from the multicenter, prospective, single-arm ANNEXA-4 trial (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) and a multicenter observational cohort study, RETRACE-II (German-Wide Multicenter Analysis of Oral Anticoagulant-Associated Intracerebral Hemorrhage - Part Two). HE was based on computed tomography scans performed within 36 hours from baseline imaging. Inverse probability of treatment weighting was performed to adjust for baseline comorbidities and ICH severity. Patients presenting with atraumatic ICH while receiving apixaban or rivaroxaban within 18 hours of admission were included. Patients with secondary ICH or not fulfilling the inclusion criteria for the ANNEXA-4 trial were excluded. We compared ANNEXA-4 patients, who received andexanet alfa for hemostatic treatment, with RETRACE-II patients who were treated with usual care, primarily administration of prothrombin complex concentrates. Primary outcome was rate of HE defined as relative increase of ≥35%. Secondary outcomes comprised mean absolute change in hematoma volume, as well as in-hospital mortality and functional outcome. Results: Overall, 182 patients with factor-Xa inhibitor–related ICH (85 receiving andexanet alfa versus 97 receiving usual care) were selected for analysis. There were no relevant differences regarding demographic or clinical characteristics between both groups. HE occurred in 11 of 80 (14%) andexanet alfa patients compared with 21 of 67 (36%) usual care patients (adjusted relative risk, 0.40 [95% CI, 0.20–0.78]; P =0.005), with a reduction in mean overall hematoma volume change of 7 mL. There were no statistically significant differences among in-hospital mortality or functional outcomes. Sensitivity analysis including only usual care patients receiving prothrombin complex concentrates demonstrated consistent results. Conclusions: As compared with usual care, andexanet alfa was associated with a lower rate of HE in atraumatic factor-Xa inhibitor–related ICH, however, without translating into significantly improved clinical outcomes. A comparative trial is needed to confirm the benefit on limiting HE and to explore clinical outcomes across patient subgroups and by time to treatment.

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Review of Prothrombin Complex Concentrates Use in Apixaban and Rivaroxaban Associated Intracranial Hemorrhages

Journal of Pharmacy Practice ◽

10.1177/08971900211015059 ◽

2021 ◽

pp. 089719002110150

Author(s):

Francisco Ibarra

Keyword(s):

Thromboembolic Event ◽

Prothrombin Complex Concentrate ◽

Factor Xa ◽

Mortality Rates ◽

Intracranial Hemorrhages ◽

Prothrombin Complex Concentrates ◽

Title 1 ◽

Study Objective ◽

Scale Scores ◽

Event Rates

Study Objective: Summarize the studies evaluating the use of 4-factor prothrombin complex concentrates in the management of apixaban and rivaroxaban associated intracranial hemorrhages. Methods: A PubMed literature search was conducted for articles published between 2013 and 2020 which contained the following terms in their title: (1) apixaban, rivaroxaban, or factor Xa inhibitor*, and (2) prothrombin complex concentrate*. Results: Eighteen observational studies were included. When a ∼25 units/kg (range: 25-26.9 units/kg) non-activated 4 factor prothrombin complex concentrate dose was administered, the hemostatic effectiveness rates were ≥ 79% in 2/4 studies that utilized the Sarode et al criteria, in comparison to 4/5 studies that administered a 50 units/kg dose. The mortality rates were < 20% in 7/9 studies with hemostatic effectiveness rates ≥ 79%. Mortality rates were lower in the studies demonstrating higher hemostatic effectiveness rates and including patients with higher Glasgow coma scale scores and lower intracerebral hemorrhage volumes. Overall, the thromboembolic event rates were 0-18%, with 16/18 studies demonstrating rates ≤ 10%. The thromboembolic event rates were not dose or agent dependent. Conclusion: Rates of hemostatic effectiveness were influenced by the definition of hemostatic effectiveness, dose administered, and patient severity. Studies suggest that higher doses may result in higher hemostatic effectiveness rates without increasing the risk of experiencing a thromboembolic event. This review may be used by providers to modify or validate their reversal strategy approach until well designed studies are available.

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The Reversal of Bleeding Caused by New Oral Anticoagulants (NOACs): A Systematic Review and Meta-Analysis

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029618796339 ◽

2018 ◽

Vol 24 (9_suppl) ◽

pp. 117S-126S ◽

Cited By ~ 5

Author(s):

Sariya Udayachalerm ◽

Sasivimol Rattanasiri ◽

Teeranan Angkananard ◽

John Attia ◽

Nakarin Sansanayudh ◽

...

Keyword(s):

Case Reports ◽

Meta Analysis ◽

Oral Anticoagulants ◽

Factor Xa ◽

New Oral Anticoagulants ◽

Thrombin Inhibitor ◽

Aggregated Data ◽

Reversal Agents ◽

Death Studies ◽

Risk Of Death

New oral anticoagulants (NOACs; ie, direct thrombin inhibitor [DTI] and factor Xa [FXa] inhibitors) were used as alternatives to warfarin. Specific antidotes (idarucizumab for dabigatran and andexanet alfa for FXa inhibitors) and hemostatic reversal agents were used for lowering bleeding, but their efficacies were still uncertain. The objectives of this study were to estimate and compare the efficacy of NOAC antidotes on bleeding reversal and death. Studies were identified from MEDLINE and Scopus databases until May 2018. Case reports/series and cohorts were selected if they assessed reversal or death rates. Data were independently extracted by 2 reviewers. Individual patient data and aggregated data of outcomes were extracted from case reports/series and cohorts. Binary regression was used to estimate outcome rates, risk ratio (RR) along with 95% confidence interval (CI). Interventions were NOACs and reversal agents (ie, DTI-specific, DTI-standard, FXa-specific, and FXa-standard). Among 220 patients of 93 case reports/series, reversal rates were 95.9%, 77.6%, and 71.5% for DTI-specific, FXa-standard, and DTI-standard. Pooled RRs for DTI-specific and FXa-standard versus DTI-standard, respectively, were 1.34 (CI: 1.13-1.60) and 1.09 (CI: 0.84-1.40). Death rate was 0.18 (CI: 0.06-0.57) times lower in DTI-specific versus DTI-standard. For pooling 10 subcohorts, pooled RRs were 1.08 (CI: 1.00-1.16), 1.29 (CI: 1.20-1.39), and 1.13 (CI: 1.01-1.25) for DTI-specific, FXa-specific, and FXa-standard versus DTI-standard. In conclusion, specific reversal agents might be useful for reversal of bleeding and lowering the risk of death than standard reversal agents. Our findings were based on case reports/series and selected cohorts, further comparative studies are thus needed.

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Reversal of Oral Anticoagulants for Intracerebral Hemorrhage Patients: Best Strategies

Seminars in Respiratory and Critical Care Medicine ◽

10.1055/s-0037-1607993 ◽

2017 ◽

Vol 38 (06) ◽

pp. 726-736 ◽

Cited By ~ 5

Author(s):

Lanting Fuh ◽

Jonathan Sin ◽

Joshua Goldstein ◽

Bryan Hayes

Keyword(s):

Intracerebral Hemorrhage ◽

Vitamin K ◽

Prothrombin Complex Concentrate ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Factor Xa ◽

Quality Data ◽

Reversal Agent ◽

Intravenous Vitamin ◽

Time Of Presentation

AbstractIn patients with acute intracerebral hemorrhage (ICH), one of the major concerns is ongoing bleeding or ICH expansion. Anticoagulated patients are at higher risk of ongoing expansion and worse outcome. It may be that rapid anticoagulation reversal can reduce the risk of expansion and improve clinical outcome. For those taking coumarins, the best available evidence suggests that intravenous vitamin K combined with four-factor prothrombin complex concentrate (4F-PCC) is the most rapid and effective regimen to restore hemostasis. For those on dabigatran, the highest quality data available for reversal are for idarucizumab, although it is not yet clear whether patients derive clinical benefit from this reversal. In the absence or failure of idarucizumab, activated prothrombin complex concentrate (aPCC) is recommended. For those on factor Xa inhibitors, the ideal reversal agent is not clear. Many providers use 4F-PCC or aPCC, but more specific agents are in clinical trials and may soon be available. In addition, the half-lives of the non–vitamin K antagonists are relatively short compared with warfarin, and so some patients may not have a clinically relevant coagulopathy at the time of presentation. Overall, the optimal reversal agent, when one is required, is a function of which anticoagulant the patient is taking.

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Bivalirudin as an Alternative to Heparin for Anticoagulation in Infants and Children

The Journal of Pediatric Pharmacology and Therapeutics ◽

10.5863/1551-6776-20.6.408 ◽

2015 ◽

Vol 20 (6) ◽

pp. 408-417 ◽

Cited By ~ 9

Author(s):

Marcia L. Buck

Keyword(s):

Life Support ◽

Extracorporeal Life Support ◽

Case Reports ◽

Pediatric Population ◽

Factor Xa ◽

Infants And Children ◽

Thrombin Inhibitor ◽

Ventricular Assist ◽

The Cost ◽

In Infants And Children

Bivalirudin, a direct thrombin inhibitor, is a useful alternative to heparin for anticoagulation in infants and children. It has been found to be effective in patients requiring treatment of thrombosis, as well as those needing anticoagulation during cardiopulmonary bypass, extracorporeal life support, or with a ventricular assist device. While it has traditionally been used in patients who were unresponsive to heparin or who developed heparin-induced thrombocytopenia, it has recently been studied as a first-line agent. Bivalirudin, unlike heparin, does not require antithrombin to be effective, and as a result, has the potential to provide a more consistent anticoagulation. The case reports and clinical studies currently available suggest that bivalirudin is as effective as heparin at reaching target activated clotting times or activated partial thromboplastin times, with equivalent or the lower rates of bleeding or thromboembolic complications. It is more expensive than heparin, but the cost may be offset by reductions in the costs associated with heparin use, including anti-factor Xa testing and the need for administration of antithrombin. The most significant disadvantage of bivalirudin remains the lack of larger prospective studies demonstrating its efficacy and safety in the pediatric population.

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Recombinant Activated Coagulation Factor VII and Prothrombin Complex Concentrates Are Equally Effective in Reducing Hematoma Volume in Experimental Warfarin-Associated Intracerebral Hemorrhage

Stroke ◽

10.1161/strokeaha.111.629360 ◽

2012 ◽

Vol 43 (1) ◽

pp. 246-249 ◽

Cited By ~ 19

Author(s):

Frieder Schlunk ◽

Elizabeth M. Van Cott ◽

Kazuhide Hayakawa ◽

Waltraud Pfeilschifter ◽

Eng H. Lo ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Coagulation Factor ◽

Factor Vii ◽

Hematoma Volume ◽

Prothrombin Complex Concentrates ◽

Coagulation Factor Vii

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Abstract P415: Is Hemostatic Efficacy of Four Factor Prothrombin Complex Concentrate Similar in Intracerebral Hemorrhage Patients Receiving Warfarin vs Non-Vitamin K Anticoagulants?

Stroke ◽

10.1161/str.52.suppl_1.p415 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Gregory Pon ◽

Brittany Pelsue ◽

Xu Zhang ◽

Brian Gulbis ◽

Sujan T Reddy ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Vitamin K ◽

Prothrombin Complex Concentrate ◽

Multivariable Analysis ◽

Chi Square ◽

Significant Difference ◽

Forward Stepwise ◽

Multivariable Regression ◽

Baseline Characteristics ◽

Hemostatic Efficacy

Introduction: Four Factor Prothrombin Complex Concentrate (4F-PCC) is indicated for reversal of warfarin-induced coagulopathy. In small cohort studies, 4F-PCC has similar hemostatic efficacy rates reversing non-vitamin K anticoagulants (NOACs). There are no comparison studies evaluating 4F-PCC for the reversal of warfarin versus NOACs in the setting of intracerebral hemorrhage (ICH). Methods: A multicenter retrospective cohort study was conducted between 2013-2020 at a comprehensive stroke system in ICH patients who received 4F-PCC for the reversal of warfarin or a NOAC. Patients were included if they were adults with an acute ICH, anticoagulant regimen of warfarin (INR 1.3 or greater) or NOAC, and 2 head CT scans within 24 hours to determine hemostatic efficacy. Hemostatic efficacy was evaluated by the Sarode scale. The chi square and t-test were used as appropriate for demographic and clinical data, with multivariable regression analysis conducted in a forward stepwise manner, retaining variables with significance less than 0.05. Results: One hundred fifty-seven patients were included (baseline characteristics in Table 1). There was no statistically significant difference in effective hemostasis observed between warfarin and NOAC patients (83% vs 75%, p=0.33). Similarly, multivariable analysis did not demonstrate a significant difference in effective hemostasis (OR 0.55, 95% CI: 0.2-1.3, p=0.2). However, due to wide 95% confidence intervals, we cannot exclude a key treatment effect from PCC. After controlling for baseline characteristics, patients treated with NOACs had 53% lower odds of a good clinical outcome compared to those treated with warfarin (Figure 1; OR 0.47, 95% CI: 0.2-1.3, p=0.13). Conclusions: In conclusion, there was no statistically significant difference in hemostatic efficacy or clinical outcomes between warfarin and NOAC patients following reversal with 4F-PCC.

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