scholarly journals Evidence-Based Minireview: Mortality and thrombosis in patients receiving prothrombin complex concentrates or andexanet alfa for the management of direct oral factor Xa inhibitor–associated major bleeding

Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 204-208 ◽  
Author(s):  
Miriam Kimpton ◽  
Deborah M. Siegal
Keyword(s):  
Computed Tomography ◽  
Major Bleeding ◽  
Factor Xa ◽  
Evidence Based ◽  
Factor Xa Inhibitor ◽  
Prothrombin Complex Concentrates ◽  
Pharmacological Agents ◽  
Previous Stroke ◽  
Level Of Consciousness ◽  
Andexanet Alfa

Abstract A 77-year-old man with atrial fibrillation and a CHA2DS2Vasc score of 6 for hypertension, age, diabetes, and previous stroke is brought to the emergency department with decreased level of consciousness. He is anticoagulated with rivaroxaban (a direct oral factor Xa inhibitor [FXaI]) and received his last dose about 4 hours before presentation. Urgent computed tomography of the head shows intracerebral hemorrhage. Because of his previous stroke, the patient’s family is concerned about treating the bleed with pharmacological agents that may increase the risk of stroke. What are the risks of thrombosis and mortality related to the use of prothrombin complex concentrates (PCCs) and andexanet alfa for patients with direct oral FXaI-associated major bleeding?

Andexanet Alfa or Prothrombin Complex Concentrate for Factor Xa Inhibitor Reversal in Acute Major Bleeding

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Charlie J. Nederpelt ◽  
Leon Naar ◽  
Pieta Krijnen ◽  
Saskia le Cessie ◽  
Haytham M. A. Kaafarani ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Prothrombin Complex Concentrate ◽  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Andexanet Alfa

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 ◽  
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.

Evaluation of the Use of Low-Dose 4-Factor Prothrombin Complex Concentrate in the Reversal of Direct Oral Anticoagulants in Bleeding Patients

2018 ◽  
Vol 35 (9) ◽  
pp. 903-908 ◽  
Author(s):  
Teresa A. Allison ◽  
Pei Jen Lin ◽  
Jennifer A. Gass ◽  
Kenneth Chong ◽  
Samuel J. Prater ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Prothrombin Complex Concentrate ◽  
Low Dose ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Final Analysis ◽  
Factor Xa Inhibitor ◽  
Direct Factor

Objective: This study investigated the percentage of patients who achieved hemostasis with 4-factor prothrombin complex concentrate (4-factor PCC) 35 U/kg. The primary end point was to determine the effect of 4-factor PCC 35 U/kg on bleeding progression, assessed using computed tomography. Methods: This was a retrospective, observational, single-center study conducted in patients with a major bleed admitted to a level 1 trauma center from May 1, 2013, to June 15, 2015, who received 4-factor PCC 35 U/kg for reversal of a direct factor Xa inhibitor taken prior to admission. Results: Thirty-three patients were included in the study, with 31 patients in the final analysis. The mean (standard deviation) age was 73 (14.8) years; 54.5% of patients were female. Of the 33 patients, 13 presented with a traumatic brain injury, 9 with an aneurysmal subarachnoid hemorrhage, 8 with an intracerebral hemorrhage, 1 with a gastrointestinal bleed, 1 with a hematoma with active extravasation, and 1 with an intra-abdominal bleed. The most frequently used direct factor Xa inhibitor was rivaroxaban (81.8%). Overall, 83.8% of patients achieved hemostasis with 4-factor PCC 35 U/kg. Progression of hemorrhage was observed in 4 patients on repeat computed tomography scan and 1 patient had continued surgical bleeding. No thromboembolic events were reported. Conclusions: Low-dose, 4-factor PCC 35 U/kg appeared to produce hemostasis in a majority of the patients. This may be an effective dosing regimen for anticoagulant reversal of factor Xa inhibitors in clinically bleeding patients.

scholarly journals Concurrent Treatment of VEGFR Tyrosine Kinase Inhibitors (TKIs) and Factor Xa Inhibitors Is Associated with Increased Bleeding Risks

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3681-3681
Author(s):  
Sandip Patel ◽  
Tiffany George ◽  
Tzu-Fei Wang ◽  
Sherry Mori Vogt ◽  
Edmund Folefac ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Major Bleeding ◽  
Metastatic Cancer ◽  
Bleeding Event ◽  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Factor Xa Inhibitor ◽  
Bleeding Events ◽  
Concurrent Treatment ◽  
Clinically Significant

ABSTRACT Background: Some cancer patients with thromboembolism require dual treatment of VEGFR TKIs and factor Xa inhibitors (direct or indirect), which may contribute to increased bleeding risks. However, the safety of such combination treatment has not been well characterized in the literature or national guidelines. Methods: This is a single center retrospective study, where we identified metastatic cancer patients (renal cancer, colorectal cancer, sarcoma, etc) who received concurrent VEGFR TKIs (pazopanib, sunitinib, sorafenib, axitinib, regorafenib, vandetanib, lenvatinib or cabozantinib) and Xa inhibitors (low-molecular weight heparin [LMWH] or direct oral anticoagulants [DOACs] including rivaroxaban or apixaban) at the Ohio State University Medical Center. We assessed bleeding risks of dual therapies vs. factor Xa inhibitors alone, using the same patients as self controls. We reviewed medical charts of all identified patients for clinically significant bleeding events (defined as combined major bleeding and clinically relevant non-major bleeding by the International Society of Thrombosis and Haemostasis criteria). The Cox proportional hazard model was used to compare the differences of time to first clinically significant bleeding event between the groups of concurrent use and anticoagulant use only. Results: A total of 86 patients (26 females and 60 males) were included: 78 Caucasians, 6 African Americans, and 2 others. 81 patients had concurrent TKI and LMWH treatment; 20 patients had concurrent TKI and DOACs; and 85 patients have had been on factor Xa inhibitor alone (LMWH or DOACs) at some point. Some patients had been on both LMWH and DOACs at different time periods. Overall, there were 29 clinically significant bleeding events (including 8 major bleeding) during concurrent treatment and 17 events (4 major bleeding) during factor Xa inhibitor alone over a median follow up of 63 days (52 days for concurrent treatment and 99 days for Xa inhibitor alone). In this self-control study, concurrent treatment was associated with a statistically higher risk of clinically significant bleeding events (HR, 2.84; 95% CI, 1.43-5.64, P < 0.01), which reached 37% patient population in the first 3 months, while the bleeding associated with factor Xa inhibitor alone seemed spaced out at the entire length of anticoagulation (8% by 6 months). Similar trend was found in the analysis of patient group of concurrent TKI and LMWH vs. LMWH alone (HR, 1.96; 95% CI, 0.95-4.02, P = 0.067), although significance was not reached likely due to insufficient power. Sample size was inadequate for meaningful comparison between concurrent VEGFR TKI and DOAC vs. DOAC alone. Conclusions: Concurrent treatment of VEGFR TKI and factor Xa inhibitors is associated with a significantly increased bleeding risks when compared with factor Xa inhibitors alone in patients with metastatic cancer. Disclosures No relevant conflicts of interest to declare.

Comment: Andexanet alfa: A Novel Factor Xa Inhibitor Reversal Agent

2019 ◽  
Vol 53 (11) ◽  
pp. 1167-1167 ◽  
Author(s):  
Brian W. Gilbert ◽  
Jacob A. Reeder
Keyword(s):  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Reversal Agent ◽  
Andexanet Alfa

scholarly journals Evaluation of oral factor Xa inhibitor‐associated extracranial bleeding reversal with andexanet alfa

2020 ◽  
Vol 18 (10) ◽  
pp. 2532-2541
Author(s):  
Charlie J. Nederpelt ◽  
Leon Naar ◽  
Katelyn W. Sylvester ◽  
Megan E. Barra ◽  
Russel J. Roberts ◽  
...  
Keyword(s):  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Andexanet Alfa

Extended Thromboprophylaxis with Rivaroxaban Compared with Short-Term Thromboprophylaxis with Enoxaparin after Total Hip Arthroplasty: The RECORD2 Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 307-307 ◽  
Author(s):  
Ajay K. Kakkar ◽  
Benjamin Brenner ◽  
Ola E. Dahl ◽  
Bengt I. Eriksson ◽  
Patrick Mouret ◽  
...  
Keyword(s):  
Total Hip Arthroplasty ◽  
Hip Arthroplasty ◽  
Major Bleeding ◽  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Primary Efficacy ◽  
Primary Efficacy Endpoint ◽  
Direct Factor ◽  
Short Term ◽  
Double Blind

Abstract Venous thromboembolism (VTE) is a common, potentially fatal complication of major orthopaedic surgery. Pharmacologic thromboprophylaxis is recommended for patients undergoing total hip arthroplasty (THA) for a minimum of 10 days, and up to 35 days. However, extended thromboprophylaxis is not universally used. Therefore, this trial was conducted to evaluate the potential benefits of extended thromboprophylaxis after THA. RECORD2 is the largest, prospective, randomized clinical trial conducted to date, in this indication. This global, phase III, double-blind trial, was designed to compare short-term thromboprophylaxis with a low molecular weight heparin - enoxaparin - with extended thromboprophylaxis for up to 5 weeks with a novel, oral, direct Factor Xa inhibitor - rivaroxaban after THA. Patients received subcutaneous enoxaparin 40 mg once daily (od), beginning the evening before surgery, continuing for 10–14 days (short-term prophylaxis), and followed by placebo until day 35±4, or oral rivaroxaban 10 mg od beginning 6–8 hours after surgery and continuing for 35±4 days (extended prophylaxis). Mandatory, bilateral venography was conducted at the end of the extended treatment period. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality. The main secondary efficacy endpoint was major VTE; the composite of proximal DVT, non-fatal PE, and VTE-related death. Major and non-major bleeding during double-blind treatment were the primary and secondary safety endpoints, respectively. A total of 2509 patients were randomized; 2457 were included in the safety population and 1733 in the modified intention-to-treat (mITT) population. Extended thromboprophylaxis with rivaroxaban was associated with a significant reduction in the incidence of the primary efficacy endpoint and major VTE, compared with short-term thromboprophylaxis with enoxaparin (Table). The incidences of major and non-major bleeding were similar in both groups (Table). In conclusion, extended duration rivaroxaban was significantly more effective than short term enoxaparin for the prevention of VTE, including major VTE, in patients undergoing THA. Furthermore, this large trial demonstrated that extended thromboprophylaxis provides substantial benefits for patients undergoing THA, and that the oral, direct Factor Xa inhibitor rivaroxaban provides a safe and effective option for such a strategy. Short-term s.c. enoxaparin 40 mg od % (n/N) Extended oral rivaroxaban 10 mg od % (n/N) Relative risk reduction (%) P-value for difference DVT, non-fatal PE, and all-cause mortalitya 9.3% (81/869) 2.0% (17/864) 79% P<0.001 Major VTEb 5.1% (49/962) 0.6% (6/961) 88% P<0.001 Major bleedingc 0.1% (1/1229) 0.1% (1/1228) - P=0.980 Non-major bleedingc 5.5% (67/1229) 6.5% (80/1228) - P=0.246

scholarly journals Effects of Andexanet Alfa on Thrombin Generation in Bleeding Associated with Factor Xa Inhibitors

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 711-711
Author(s):  
Michiel Coppens ◽  
Lizhen Xu ◽  
Roisin Bavalia ◽  
Saskia Middeldorp ◽  
Peter Verhamme ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Thrombin Generation ◽  
Factor Xa ◽  
Educational Material ◽  
Factor Xa Inhibitor ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Andexanet Alfa

Introduction Andexanet alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors. In the ANNEXA-4 study, patients with acute major bleeding within 18 h after administration of a factor Xa inhibitor were enrolled and received a bolus of andexanet, followed by a 2-h infusion (Connolly, NEJM 2019;380:1326). In this study, 82% of patients achieved effective hemostasis at 12 h and 10% developed a thrombotic event within 30 days. Anti-Xa activity decreased by 92% after the andexanet bolus but partially recovered after the end of the 2 h infusion. In the present analysis, we evaluated the effect of andexanet alfa on thrombin generation (TG) in patients enrolled in the ANNEXA-4 study and we explored whether TG predicts effective hemostasis or thrombotic events. Methods We included all patients who received andexanet alfa. TG was expressed as the endogenous thrombin potential (ETP) which is the area under the thrombin generation curve. We plotted mean TG at different timepoints between baseline and 30 days after andexanet alfa in patients treated with apixaban and rivaroxaban. We compared the absolute ETP level at 8 h (ETP-8H) after andexanet bolus as this was the first timepoint after the 2 h infusion for which an ETP level was available for most patients. We compared ETP-8H levels between patients with and without effective hemostasis and between those with and without thrombotic events, respectively. ETP-8H was evaluated as a predictor of effective hemostasis and thrombotic events by logistic regression analysis in all patients, and in subgroups of patients with intracranial hemorrhage (ICH) and non-ICH separately. In the ICH subgroups, ETP-8H was also evaluated as a predictor of absolute change in hematoma volume. Results The study population comprised 352 patients (mean age 77.4 years; 47% female) with acute major bleeding (64% ICH, 26% gastrointestinal, 10% other) treated with apixaban (55%), rivaroxaban (36%), enoxaparin (6%), or edoxaban (3%). ETP-8H was available for 327 patients (93%). In patients treated with apixaban or rivaroxaban, andexanet bolus promptly increased mean ETP and this was maintained during infusion. After end of infusion ETP fell but remained in the reference range for at least 18 hours (Figure 1). ETP-8H was similar in patients with or without effective hemostasis (Fig 2a, p = 0.544) and in patients with or without thrombotic complications (Fig 2b, p = 0.610). In the logistic regression analysis, ETP-8H did not predict effective hemostasis (p=0.491) or thrombotic events (p=0.743) (Table), and these results were consistent in ICH and non-ICH patients. ETP-8H did not predict hematoma growth in patients with ICH (p = 0.349). Conclusion A bolus of andexanet alfa, followed by a 2-h infusion in patients with factor Xa inhibitor associated major bleeding promptly restores thrombin generation and this effect is sustained for at least 18 hours. Thrombin generation at 8 h after andexanet bolus did not predict effective hemostasis, intracranial hematoma growth, or thrombotic events. This may be explained by the andexanet dose which was chosen to ensure full reversal of the factor Xa inhibitor in all patients. Disclosures Coppens: Bayer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Sanquin Blood Supply: Research Funding; Pfizer: Honoraria; Uniqure: Research Funding; CSL Behring: Honoraria, Research Funding; Portola Pharmaceuticals, Inc: Honoraria; Boehringer Ingelheim: Research Funding. Middeldorp:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: honoraria for advisory activities; Aspen: Research Funding; Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: honoraria for advisory activities; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Other: honoraria for advisory activities; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: honoraria for advisory activities, Research Funding; Sanofi: Speakers Bureau; Daiichi Sankyo: Other: honoraria for advisory activities, Research Funding. Verhamme:Portola Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer Healthcare: Consultancy, Research Funding, Speakers Bureau; Boehringer Ingelheim: Consultancy, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Leo Pharma: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy. Eikelboom:Heart and Stroke Foundation: Research Funding; Sanofi Aventis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Glaxo Smith Kline: Honoraria, Research Funding; Eli Lilly: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding. Crowther:Bayer: Other: Data and Safety Monitoring Board, Research Funding, Speakers Bureau; BMS Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Other: preparing educational material and/or providing educational presentations; CSL Behring: Other: preparing educational material and/or providing educational presentations; Diagnostica Stago: Other: preparing educational material and/or providing educational presentations, Research Funding; Alnylam: Equity Ownership; Asahi Kasei: Membership on an entity's Board of Directors or advisory committees; Alexion: Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees. Lu:Portola Pharmaceuticals: Employment, Equity Ownership. Yue:Portola Pharmaceuticals: Employment, Equity Ownership. Conley:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership. Connolly:Portola Pharmaceuticals: Consultancy, Research Funding; Bayer Healthcare: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding.

A Systematic and Evidence-Based Review of Published and Pending Reports of Andexanet Alfa

2019 ◽  
Vol 33 (4) ◽  
pp. 465-470 ◽  
Author(s):  
Thomas M. Ellington
Keyword(s):  
Clinical Trials ◽  
Factor Xa ◽  
Moderate Level ◽  
Evidence Based ◽  
Reversal Agent ◽  
Level Of Evidence ◽  
Low Level ◽  
Life Threatening ◽  
Andexanet Alfa ◽  
Active Research

Andexanet alfa is the newly approved factor Xa inhibitor reversal agent for the treatment of life-threatening or uncontrolled bleeding from apixaban or rivaroxaban. This decoy protein directly binds factor Xa inhibitors reversing their action. A systematic and evidence-based evaluation of the available clinical trials is lacking in the literature. This research will provide a systematic and evidence-based evaluation of published clinical trials for andexanet alfa. It will also present an evaluation of active research. Reports of research were identified through multiple databases using search terms andexanet alfa, andexanet, or PRT064445. The level of evidence and strength of recommendation were accomplished using the Strength of Recommendation Taxonomy. There are 2 published articles presenting 3 clinical trials. Two trials had a low level of evidence and the third trial, a preliminary report of results, showed a moderate level of evidence. The review of active research found 3 unique studies and a preliminary results study. The level of evidence is low for 2 of these studies, moderate for a third, and potentially high for the fourth. The strength of recommendation for all 6 studies is a C. Four of the studies present disease-oriented evidence resulting in a low level of evidence. Another study is unblinded and uncontrolled but presents patient-oriented evidence resulting in a moderate level of evidence. Only one study could score high because the outcome is patient-oriented evidence, and it could achieve follow-up of 80%. There is a need for well-controlled and blinded evaluation to improve the recommendation strength.

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