Prothrombin Complex Concentrate for Major Bleeding on Factor Xa Inhibitors: A Prospective Cohort Study

AbstractOral factor Xa inhibitors are increasingly used for anticoagulation, but there is no approved reversal agent. Prothrombin complex concentrate (PCC) for the management of Xa-inhibitor–associated bleeding has been described in small case series and one cohort study. Patients on apixaban or rivaroxaban, suffering a major bleed, were treated at nine Canadian hospitals as per existing hospital protocol with a fixed dose of PCC 2,000 units and subsequently recruited for a 30-day follow-up. The treating physician evaluated the haemostatic effectiveness as observed during the first day as good, moderate or poor/none, using an assessment guide. Safety outcomes were thromboembolism or death. We recruited 66 patients with major bleeding who were treated with PCC and who were receiving rivaroxaban (56%) or apixaban (44%). The effectiveness was assessed as good in 65% (95% confidence interval [CI], 53–77), moderate in 20% (95% CI, 10–30) and poor/none in 15% (95% CI, 6–24). For the 36 patients with intracranial haemorrhage, the corresponding ratings were 67, 17 and 17%, and for 16 patients with gastrointestinal bleeding they were 69, 12 and 19%, respectively. There were nine deaths (14%) by 30 days, and five (8%) major thromboembolic events. In a post hoc analysis, according to International Society on Thrombosis and Haemostasis criteria, reversal was effective in 68% and ineffective in 32%. For major bleeding associated with oral Xa inhibitors, PCC may have a beneficial effect. The risk of thromboembolism after reversal of anticoagulation in patients with a prothrombotic background has to be taken into account.

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Erratum to: Prothrombin Complex Concentrate for Major Bleeding on Factor Xa Inhibitors: A Prospective Cohort Study

Thrombosis and Haemostasis ◽

10.1055/s-0038-1675417 ◽

2018 ◽

Vol 118 (12) ◽

pp. 2188-2188 ◽

Cited By ~ 18

Author(s):

Sam Schulman ◽

Peter Gross ◽

Bruce Ritchie ◽

Susan Nahirniak ◽

Yulia Lin ◽

...

Keyword(s):

Cohort Study ◽

Prospective Cohort Study ◽

Major Bleeding ◽

Prospective Cohort ◽

Prothrombin Complex Concentrate ◽

Factor Xa ◽

Factor Xa Inhibitors

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

Journal of Thrombosis and Thrombolysis ◽

10.1007/s11239-021-02536-x ◽

2021 ◽

Author(s):

Pallavi Dev ◽

Carol Abousaab ◽

Cecilia Zhou ◽

Ravi Sarode

Keyword(s):

Prothrombin Complex Concentrate ◽

Factor Xa ◽

Factor Xa Inhibitors ◽

Major Bleed

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Management of direct factor Xa inhibitor–related major bleeding with prothrombin complex concentrate: a meta-analysis

Blood Advances ◽

10.1182/bloodadvances.2018024133 ◽

2019 ◽

Vol 3 (2) ◽

pp. 158-167 ◽

Cited By ~ 41

Author(s):

Siavash Piran ◽

Rasha Khatib ◽

Sam Schulman ◽

Ammar Majeed ◽

Anne Holbrook ◽

...

Keyword(s):

Major Bleeding ◽

Prothrombin Complex Concentrate ◽

Meta Analysis ◽

Case Series ◽

Factor Xa ◽

The United States ◽

Effective Management ◽

Direct Factor ◽

All Cause Mortality ◽

Fxa Inhibitor

Abstract A targeted antidote for reversal of direct factor Xa (FXa) inhibitors is now available for clinical use in the United States, but it is costly and has limited availability. In a systematic review, we evaluated the safety and effectiveness of 4-factor prothrombin complex concentrate (4F-PCC) as an alternative for managing direct FXa inhibitor–related major bleeding. A systematic literature search was conducted using Medline, Embase, and the Cochrane Register of Controlled Trials up to September 2018. No comparative studies were found. Ten case series with 340 patients who received PCC for direct FXa inhibitor–related major bleeding were included. The pooled proportion of patients with effective management of major bleeding was 0.69 (95% confidence interval [CI], 0.61-0.76) in 2 studies using the International Society on Thrombosis and Haemostasis (ISTH) criteria and 0.77 (95% CI, 0.63-0.92) in 8 studies that did not use the ISTH criteria; all-cause mortality was 0.16 (95% CI, 0.07-0.26), and thromboembolism rate was 0.04 (95% CI, 0.01-0.08). On the basis of evidence with very low certainty from single-arm case series, it is difficult to determine whether 4F-PCC in addition to cessation of direct oral FXa inhibitor is more effective than cessation of direct oral FXa inhibitor alone in patients with direct FXa inhibitor–related major bleeding.

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Andexanet alfa is an effective reversal agent for factor Xa inhibitors in patients that develop intracranial hemorrhage

Clinical Research in Practice The Journal of Team Hippocrates ◽

10.22237/crp/1567555500 ◽

2019 ◽

Vol 5 (2) ◽

Author(s):

Joseph Friedli

Keyword(s):

Clinical Application ◽

Intracranial Hemorrhage ◽

Major Bleeding ◽

Critical Appraisal ◽

Factor Xa ◽

Factor Xa Inhibitors ◽

Reversal Agent ◽

Andexanet Alfa

<p>A critical appraisal and clinical application of Connolly SJ, Milling TJ, Eikelboom JW, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. <em>N Engl J Med</em>. 2016;375(12):1131-1141. doi: <a href="https://doi.org/10.1056/NEJMoa1607887">10.1056/NEJMoa1607887</a>.</p>

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Utilization of 4-Factor Prothrombin Complex Concentrate for Reversal of Oral Factor Xa Inhibitor–Associated Acute Major Bleeding: A Case Series

Journal of Pharmacy Practice ◽

10.1177/0897190020907012 ◽

2020 ◽

pp. 089719002090701

Author(s):

Tessa R. Reynolds ◽

Brian W. Gilbert ◽

Katherine M. Hall

Keyword(s):

Major Bleeding ◽

Prothrombin Complex Concentrate ◽

Thrombotic Event ◽

Safety Data ◽

Case Series ◽

Factor Xa ◽

Retrospective Case ◽

Point Analysis ◽

Dosing Regimens ◽

Fxa Inhibitor

Objective: In cases of oral factor Xa (FXa) inhibitor–associated acute major bleeding, several reversal strategies are available. Current guidelines recommend a dose of 50 U/kg if using 4-factor prothrombin complex concentrate (4F-PCC). A paucity of data exists with the use of 4F-PCC for FXa inhibitor reversal for acute major bleeding, specifically the most efficacious dosing regimens and safety data. The purpose of this case series is to describe the utilization of 4F-PCC for reversal of oral FXa inhibitor–associated acute major bleeding. Methods: This retrospective case series included all admitted patients 18 years and older who received 4F-PCC for oral FXa inhibitor–associated major bleeding. Major bleeding was defined using the International Society of Thrombosis and Hemostasis definition for major bleeding in nonsurgical patients. The primary outcome was achievement of hemostasis. Results: A total of 31 patients met inclusion criteria, with 17 receiving rivaroxaban and 14 receiving apixaban. Intracranial hemorrhage was the most common type of bleeding occurring in 15 (55%) patients. The median dose of 4F-PCC was 37 U/kg. Of the patients evaluated in the primary end point analysis, 68% achieved effective hemostasis. Four (12.9%) patients experienced a documented thrombotic event within 7 days of receiving 4F-PCC. Conclusion: The use of 4F-PCC for FXa inhibitor–associated acute major bleeding was effective for the majority of patients. The rate of thrombotic events appears higher compared to previously published studies, although major confounders exist and larger studies are needed to fully evaluate the safety of 4F-PCC for this indication.

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Management of major bleeding in patients treated with direct oral anticoagulants: from experience to standardized protocols

Italian Journal of Medicine ◽

10.4081/itjm.2020.1224 ◽

2020 ◽

Vol 14 (2) ◽

pp. 43-48

Author(s):

Sara Mascia ◽

Anna Maria Ferrari ◽

Nicola Macarone Palmieri ◽

Elisa Romagnoli ◽

Chiara Catena ◽

...

Keyword(s):

Major Bleeding ◽

Prothrombin Complex Concentrate ◽

Clinical Laboratory ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Laboratory Data ◽

Factor Xa ◽

Drug Dosage ◽

Reversal Agent ◽

Santa Maria

Evaluation of clinical-laboratory-therapeutic management and related clinical outcomes (thrombotic-hemorrhagic complications) of patients undergoing treatment with direct oral anticoagulants (DOACs) during major bleeding. This is a two-year observational retrospective study. 27 cases of major bleeding in patients undergoing a therapy with DOACs presented to the Emergency Department of Arcispedale Santa Maria Nuova (Reggio Emilia Hospital). 16 cases (59%) underwent reversal of anticoagulation treatment: 19% using specific reversal therapy (idarucizumab) and 81% using non-specific agents [4-factor prothrombin complex concentrate (4F-PCC)]. Routine laboratory data were available for all the cases, but only for some patients it was possible to obtain the plasma dosage of the oral anticoagulant. Laboratory data confirm rapid correction of activated partial thromboplastin time within one hour from the reversal of anticoagulation with idarucizumab. The absence of correlation between standard blood tests and plasma drug dosage in patients treated with factor Xa Inhibitors was confirmed too. The management of major bleeding during treatment with DOACs using reversal therapy (idarucizumab) and non-specific reversal agent (4F-PCC) showed minimal thrombotic (0.3%) and hemorrhagic (0.3%) complications at 90 days; no events occurred after 6 months.

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A meta‐analysis of andexanet alfa and prothrombin complex concentrate in the treatment of factor Xa inhibitor–related major bleeding

Research and Practice in Thrombosis and Haemostasis ◽

10.1002/rth2.12518 ◽

2021 ◽

Vol 5 (4) ◽

Author(s):

Tessa Jaspers ◽

Kimberly Shudofsky ◽

Menno V. Huisman ◽

Karina Meijer ◽

Nakisa Khorsand

Keyword(s):

Major Bleeding ◽

Prothrombin Complex Concentrate ◽

Meta Analysis ◽

Factor Xa ◽

Factor Xa Inhibitor ◽

Andexanet Alfa

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

Blood ◽

10.1182/blood-2019-130465 ◽

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.

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