Reversal Of Direct Oral Anticoagulants Research Articles

A small-molecule hemostatic agent for the reversal of direct oral anticoagulant–induced bleeding

BackgroundThe bleeding risk associated with direct oral anticoagulants (DOACs) remains a major concern, and rapid reversal of anticoagulant activity may be required. Although specific and nonspecific hemostatic biotherapies are available, there is a need for small-molecule DOAC reversal agents that are simple and cost-effective to produce, store, and administer. ObjectivesTo identify and characterize a small molecule with procoagulant activity as a DOAC reversal agent. MethodsWe sought to identify a small procoagulant molecule by screening a chemical library with a plasma clotting assay. The selected molecule was assessed for its procoagulant properties and its ability to reverse the effects of the DOACs in a thrombin generation assay. Its activity as a DOAC reversal agent was also evaluated in a tail-clip bleeding assay in mice. ResultsThe hemostatic molecule (HeMo) dose-dependently promoted thrombin generation in plasma, with dose values effective in producing half-maximum response ranging between 3 and 5 μM, depending on the thrombin generation assay parameter considered. HeMo also restored impaired thrombin generation in DOAC-spiked plasma and reversed DOAC activity in the mouse bleeding model. HeMo significantly reduced apixaban-induced bleeding from 709 to 65 μL (vs 43 μL in controls; P < .01) and dabigatran-induced bleeding from 989 to 155 μL (vs 126 μL in controls; P < .01). ConclusionHeMo is a small-molecule procoagulant that can counterbalance hemostatic disruption by a thrombin inhibitor (dabigatran) or factor Xa inhibitors (apixaban and rivaroxaban). The compound’s effective clot formation and versatility make it a possible option for managing the inherent hemorrhagic risk during DOAC therapy.

Clinical guideline on reversal of direct oral anticoagulants in patients with life threatening bleeding.

Anticoagulation is essential for the treatment and prevention of thromboembolic events. Current guidelines recommend direct oral anticoagulants (DOACs) over vitamin K antagonists in DOAC-eligible patients. The major complication of anticoagulation is serious or life-threatening haemorrhage, which may necessitate prompt haemostatic intervention. Reversal of DOACs may also be required for patients in need of urgent invasive procedures. This guideline from the European Society of Anaesthesiology and Intensive Care (ESAIC) aims to provide evidence-based recommendations and suggestions on how to manage patients on DOACs undergoing urgent or emergency procedures including the treatment of DOAC-induced bleeding. A systematic literature search was performed, examining four drug comparators (dabigatran, rivaroxaban, apixaban, edoxaban) and clinical scenarios ranging from planned to emergency surgery with the outcomes of mortality, haematoma growth and thromboembolic complications. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology was used to assess the methodological quality of the included studies. Consensus on the wording of the recommendations was achieved by a Delphi process. So far, no results from prospective randomised trials comparing two active comparators (e.g. a direct reversal agent and an unspecific haemostatic agent such as prothrombin complex concentrate: PCC) have been published yet and the majority of publications were uncontrolled and observational studies. Thus, the certainty of evidence was assessed to be either low or very low (GRADE C). Thirty-five recommendations and clinical practice statements were developed. During the Delphi process, strong consensus (>90% agreement) was achieved in 97.1% of recommendations and consensus (75 to 90% agreement) in 2.9%. DOAC-specific coagulation monitoring may help in patients at risk for elevated DOAC levels, whereas global coagulation tests are not recommended to exclude clinically relevant DOAC levels. In urgent clinical situations, haemostatic treatment using either the direct reversal or nonspecific haemostatic agents should be started without waiting for DOAC level monitoring. DOAC levels above 50 ng ml-1 may be considered clinically relevant necessitating haemostatic treatment before urgent or emergency procedures. Before cardiac surgery under activated factor Xa (FXa) inhibitors, the use of andexanet alfa is not recommended because of inhibition of unfractionated heparin, which is needed for extracorporeal circulation. In the situation of DOAC overdose without bleeding, no haemostatic intervention is suggested, instead measures to eliminate the DOACs should be taken. Due to the lack of published results from comparative prospective, randomised studies, the superiority of reversal treatment strategy vs. a nonspecific haemostatic treatment is unclear for most urgent and emergency procedures and bleeding. Due to the paucity of clinical data, no recommendations for the use of recombinant activated factor VII as a nonspecific haemostatic agent can be given. In the clinical scenarios of DOAC intake before urgent procedures and DOAC-induced bleeding, practitioners should evaluate the risk of bleeding of the procedure and the severity of the DOAC-induced bleeding before initiating treatment. Optimal reversal strategy remains to be determined in future trials for most clinical settings.

Four-factor prothrombin complex concentrate versus andexanet alfa for the reversal of traumatic brain injuries

BackgroundAndexanet alfa was approved in 2018 for reversal of direct oral anticoagulants but due to issues of cost and access, four-factor prothrombin complex concentrate (4F-PCC) continues to be used for...

Optimal management of cardiac surgery patients using direct oral anticoagulants: recommendations for clinical practice.

Literature is scarce on the management of patients using direct oral anticoagulants (DOACs) undergoing elective, urgent and emergency surgery. Therefore, we summarize the current evidence and provide literature-based recommendations for the management of patients on DOACs in the perioperative phase. A general literature review was conducted on the pharmacology of DOACs and for recommendations on the management of cardiac surgical patients on DOACs. Additionally, we performed a systematic review for studies on the use of direct DOAC reversal agents in the emergency cardiac surgical setting. When surgery is elective, the DOAC cessation strategy is relatively straightforward and should be adapted to the renal function. The same approach applies to urgent cases, but additional DOAC activity drug level monitoring tests may be useful. In emergency cases, idarucizumab can be safely administered to patients on dabigatran in any of the perioperative phases. However, andexanet alfa, which is not registered for perioperative use, should not be administered in the preoperative phase to reverse the effect of factor Xa inhibitors, as it may induce temporary heparin resistance. Finally, the administration of (activated) prothrombin complex concentrate may be considered in all patients on DOACs, and such concentrates are generally readily available. DOACs offer several advantages over vitamin K antagonists, but care must be taken in patients undergoing cardiac surgery. Although elective and urgent cases can be managed relatively straightforwardly, the management of emergency cases requires particular attention.

Propensity matched analysis examining the effect of passive reversal of direct oral anticoagulants on blood loss and the need for transfusions among traumatic geriatric hip fractures

BackgroundReversal of direct oral anticoagulants (DOACs) is currently recommended prior to emergent surgery, such as surgical intervention for traumatic geriatric hip fractures. However, reversal methods are expensive and timely, often delaying surgical intervention, which is a predictor of outcomes. The study objective was to examine the effect of DOAC reversal on blood loss and transfusions among geriatric patients with hip fractures.MethodsThis retrospective propensity-matched study across six level I trauma centers included geriatric patients on DOACs with isolated fragility hip fractures requiring surgical intervention (2014–2017). Outcomes included: intraoperative blood loss, intraoperative pRBCs, and hospital length of stay (HLOS).ResultsAfter matching there were 62 patients (31 reversed, 31 not reversed), 29 patients were not matched. The only reversal method utilized was passive reversal (waiting ≥ 24 hours for elimination). Passively reversed patients had a longer time to surgery (mean, 43 vs. 18 hours, p < 0.01). Most patients (92%) had blood loss (90% passively reversed, 94% not reversed); the median volume of blood loss was 100 mL for both those groups, p = 0.97. Thirteen percent had pRBCs transfused (13% passively reversed and 13% not reversed); the median volume of pRBCs transfused was 525 mL for those passively reversed and 314 mL for those not reversed, p = 0.52. The mean HLOS was significantly longer for those passively reversed (7 vs. 5 days, p = 0.001).ConclusionsPassive DOAC reversal for geriatric patients with isolated hip fracture requiring surgery may be contributing to delayed surgery and an increased HLOS without having a significant effect on blood loss or transfusions. These data suggest that passive DOAC reversal may not be necessary prior to surgical repair of isolated hip fracture.

Andexanet alfa and heparin resistance in cardiac surgery: Experiences and risks associated with the reversal of direct oral anticoagulants.

Journal Article Accepted manuscript Andexanet Alfa and Heparin Resistance in Cardiac Surgery: Experiences and risks associated with the reversal of direct oral anticoagulants Get access Daniel-Sebastian Dohle, Daniel-Sebastian Dohle Department of Cardiovascular Surgery, Johannes-Gutenberg University, Mainz, Germany Corresponding author: Daniel-Sebastian Dohle, MD, PhD, Department of Cardiovascular Surgery, Heart Center Mainz, University Hospital Mainz, Langenbeckstraße 1, 55122 Mainz, Germany, Tel: 0049 6131 17 2735 E-Mail: Daniel-Sebastian.Dohle@unimedizin-mainz.de Search for other works by this author on: Oxford Academic PubMed Google Scholar Philipp Pfeiffer, Philipp Pfeiffer Department of Cardiovascular Surgery, Johannes-Gutenberg University, Mainz, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Chris Probst, Chris Probst Department of Cardiovascular Surgery, Johannes-Gutenberg University, Mainz, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Hendrik Treede Hendrik Treede Department of Cardiovascular Surgery, Johannes-Gutenberg University, Mainz, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar European Journal of Cardio-Thoracic Surgery, ezad189, https://doi.org/10.1093/ejcts/ezad189 Published: 05 May 2023 Article history Received: 24 April 2023 Accepted: 04 May 2023 Published: 05 May 2023

When and How to Use Reversal Agents for Direct Oral Anticoagulants?

Our objective is to describe currently available reversal agents for direct oral anticoagulants (DOACs), their target population, the available clinical practice recommendations and future directions. Specific (idarucizumab for dabigatran and andexanet alfa for direct factor Xa inhibitors) and non-specific (prothrombin complex concentrates) reversal agents are effective in neutralizing the anticoagulant effect of DOACs. New investigational antidotes such as ciraparantag and VMX-C001 offer an alternative to andexanet alfa in reversing the anticoagulant activity of direct oral factor Xa inhibitors, but more clinical data are needed before they could be licensed for use. Specific reversal agents are recommended for use in clinical situations within their licensed indications (i.e.: reversal of DOACs in patients with severe uncontrolled or life-threatening bleeding or in need of emergency surgery or other invasive procedures), while non-specific reversal agents may be used when specific antidotes are not available or indicated.

Direct Oral Anticoagulants: Laboratory Challenges and Antidotes.

The use of direct oral anticoagulants (DOACs) is increasing in patients needing treatment of venous thromboembolism (VTE) and stroke prevention in atrial fibrillation (SPAF). This is due to the net clinical benefit in comparison to vitamin K antagonists (VKAs). The rise in DOAC use is accompanied by a remarkable reduction in heparin and VKA prescriptions. However, this rapid change in anticoagulation patterns brought new challenges to patients, prescribers, laboratories, and emergency physicians. Patients have new liberties concerning nutritional habits and comedication and no longer need frequent monitoring or dose adjustments. Still, they have to comprehend that DOACs are potent anticoagulants that may cause or contribute to bleeding. Challenges for the prescriber include decision pathways for choosing the right anticoagulant and dosage for a specific patient and to change bridging practice in case of invasive procedures. Laboratory personnel are challenged by DOAC due to limited 24/7 availability of specific DOAC quantification tests and by the impact of DOAC on routine coagulation assays and thrombophilia tests. Challenges for the emergency physician result from the increasing age of DOAC anticoagulated patients, the difficulties to establish last intake of DOAC type and dosage, to interpret coagulation test results in emergency situations, and to make decisions for or against DOAC reversal strategies in acute bleeding or urgent surgery. In conclusion, although DOACs make long-term anticoagulation safer and more convenient for patients, DOACs pose challenge to all healthcare providers involved in anticoagulation decisions. The key to correct patient management and optimal outcome therefore lies in education.

Intravenous Thrombolysis in Patients With Ischemic Stroke and Recent Ingestion of Direct Oral Anticoagulants

International guidelines recommend avoiding intravenous thrombolysis (IVT) in patients with ischemic stroke who have a recent intake of a direct oral anticoagulant (DOAC). To determine the risk of symptomatic intracranial hemorrhage (sICH) associated with use of IVT in patients with recent DOAC ingestion. This international, multicenter, retrospective cohort study included 64 primary and comprehensive stroke centers across Europe, Asia, Australia, and New Zealand. Consecutive adult patients with ischemic stroke who received IVT (both with and without thrombectomy) were included. Patients whose last known DOAC ingestion was more than 48 hours before stroke onset were excluded. A total of 832 patients with recent DOAC use were compared with 32 375 controls without recent DOAC use. Data were collected from January 2008 to December 2021. Prior DOAC therapy (confirmed last ingestion within 48 hours prior to IVT) compared with no prior oral anticoagulation. The main outcome was sICH within 36 hours after IVT, defined as worsening of at least 4 points on the National Institutes of Health Stroke Scale and attributed to radiologically evident intracranial hemorrhage. Outcomes were compared according to different selection strategies (DOAC-level measurements, DOAC reversal treatment, IVT with neither DOAC-level measurement nor idarucizumab). The association of sICH with DOAC plasma levels and very recent ingestions was explored in sensitivity analyses. Of 33 207 included patients, 14 458 (43.5%) were female, and the median (IQR) age was 73 (62-80) years. The median (IQR) National Institutes of Health Stroke Scale score was 9 (5-16). Of the 832 patients taking DOAC, 252 (30.3%) received DOAC reversal before IVT (all idarucizumab), 225 (27.0%) had DOAC-level measurements, and 355 (42.7%) received IVT without measuring DOAC plasma levels or reversal treatment. The unadjusted rate of sICH was 2.5% (95% CI, 1.6-3.8) in patients taking DOACs compared with 4.1% (95% CI, 3.9-4.4) in control patients using no anticoagulants. Recent DOAC ingestion was associated with lower odds of sICH after IVT compared with no anticoagulation (adjusted odds ratio, 0.57; 95% CI, 0.36-0.92). This finding was consistent among the different selection strategies and in sensitivity analyses of patients with detectable plasma levels or very recent ingestion. In this study, there was insufficient evidence of excess harm associated with off-label IVT in selected patients after ischemic stroke with recent DOAC ingestion.

Retrospective review of Andexanet Alfa versus 4-Factor Prothrombin Complex Concentrate for reversal of DOAC-Associated Intracranial Hemorrhage

Background: Mortality of oral anticoagulation-associated ICH is around 60%, with oral anticoagulation increasing the risk of ICH seven to ten-fold compared to no anticoagulation. Current guidelines recommend DOACs (direct oral anticoagulants) as first-line therapy in the treatment of VTE (Venous Thromboembolism) due to their more favorable safety profile. There are two agents available for DOAC reversal, Coagulation Factor Xa (recombinant), inactivated-zhzo (andexanet alfa, Andexxa®) and 4-factor prothrombin complex concentrate (4FPCC). There is little data comparing the two agents in real-life clinical settings.Objective: The primary objective of this study was to determine if there was a difference in hemostatic efficacy of andexanet alfa and 4FPCC in patients with a factor Xa inhibitor-related intracranial hemorrhage.Methods: This was a retrospective, single-center study conducted in adult patients admitted at a quaternary academic medical center from September 2017 to March 2021. Adults with a diagnosis of intracranial hemorrhage (ICH) were included if they received either 4FPCC or andexanet alfa for reversal of apixaban or rivaroxaban. In addition to hemostatic efficacy per imaging, we assessed disposition location, cerebral performance score, blood product consumption, and the development of a new thrombus.Results: A total of 46 patients were included in this study, 15 received 4FPCC (32%) and 31 received andexanet alfa (68%). There was no difference in the proportion of patients with excellent (4FPCC 9 [60%] vs. andexanet alfa 16 [51.6%], p = 0.61), good (4FPCC 2 [13.3%] vs. andexanet alfa 7 [22.6%]), or poor (4FPCC 1 [6.7%] vs. andexanet alfa 5 [16.1%]) hemostasis after administration of each agent. There were no significant differences in any secondary outcomes.Conclusion and Relevance: Our study found no difference in hemostatic efficacy between andexanet alfa and 4FPCC. At this time, clinicians should choose an agent based on individual patient presentation and resource availability. Further research will help clarify the role of each agent in the management of DOAC-related intracranial hemorrhage.

Direct Oral Anticoagulant Reversal in the Pediatric Emergency Department.

Direct Oral Anticoagulant Reversal in the Pediatric Emergency Department.

Reversing direct factor Xa or thrombin inhibitors: Factor V addition to prothrombin complex concentrate is beneficial in vitro

BackgroundProthrombin complex concentrate (PCC) is a human plasma‐derived mixture of partially purified vitamin K‐dependent coagulation factors (VKCF). Current therapeutic indication is treatment and perioperative prophylaxis of bleeding in acquired VKCF deficiency. Off‐label uses include treatment of direct factor Xa‐ or thrombin inhibitor‐associated bleeds, treatment of trauma‐induced coagulopathy, and hemorrhagic complications in patients with liver disease. ObjectiveConsidering PCC as a general prohemostatic drug, we argued that its clinical efficacy can benefit from supplementation with coagulation factors that are absent in the current PCC formulation. In this study, we focused on factor V. MethodsWe mimicked a coagulopathy in vitro by spiking whole blood or derived plasma with the direct oral anticoagulants (DOAC) rivaroxaban or dabigatran. We studied DOAC reversal by PCC and factor V concentrate (FVC) using a thrombin generation assay, thromboelastography, fibrin generation clot lysis test, and microfluidic thrombus formation under flow. ResultsIn DOAC‐treated plasma, PCC increased the amount of thrombin generated. The addition of FVC alone or in combination with PCC caused a partial correction of the thrombin generation lag time and clotting time. In DOAC‐treated whole blood, the combination of PCC and FVC synergistically improved clotting time under static conditions, whereas complete correction of fibrin formation was observed under flow. Clot strength and clot resistance toward tissue plasminogen activator‐induced lysis were both increased with PCC and further enhanced by additional FVC. ConclusionOur in vitro study demonstrates a beneficial effect of the combined use of PCC and FVC in DOAC reversal.

New agents for DOAC reversal: a practical management review.

Bleeding is the commonest and most concerning adverse event associated with anticoagulants. Bleeding, depending on the severity, is managed in various ways, and for severe or life-threatening bleeding, specific antidotes are indicated and recommended. This review provides guidance relating to specific direct oral anticoagulant (DOAC) reversal agents, the antidotes. We discuss their indications for use, dosing, and potential side effects.

Therapeutic Plasma Exchange for Apixaban Removal in the Setting of Delayed Clearance and Life-Threatening Bleeding

Introduction:The management of bleeding associated with direct oral anticoagulants (DOACs) is challenging and associated with high risk of morbidity/mortality despite the use of various reversal agents (Gomez-Outes et al. 2021). Routine tests cannot determine the level of DOAC anticoagulation and reversal agents carry potential prothrombotic complications (Garcia & Crowther 2021). We present an unusual case of a patient requiring emergent surgery with significant post-op bleeding due to profoundly delayed apixaban elimination.Case Description:A 63-year-old female presented to the emergency department (ED) with a 10-day history of worsening abdominal pain, distension, nausea and constipation. Her past medical history was notable for right sided heart failure, COVID-19 pneumonia requiring intubation, tissue mitral valve replacement, and post-op atrial fibrillation for which she was prescribed apixaban 5 mg BID. Her last dose of apixaban had been the night prior to ED presentation.In the ED, a CT of the abdomen revealed a 6 cm partially obstructing lesion involving the mid-sigmoid colon. Findings were consistent with evolving peritonitis and the patient underwent an emergent exploratory laparotomy, sigmoid resection, and end colostomy. Pre-op labs revealed WBC 12.4 x10 9/L, hemoglobin (hgb) 9.2 g/dL, and platelets 318 x10 9/L. Coagulation studies revealed a PT of 28 sec and INR of 2.5. The patient was given prothrombin complex concentrate (PCC) 25 units/kg and 1 mg of vitamin K prior to surgery. Postoperatively, the INR remained elevated, 2.0, and her hgb downtrended from 8.8 g/dL to 7.8 g/dL. On post-op day 1 the patient became hypotensive, with increased abdominal pain/distension, she also started bleeding from her ostomy. The INR was 2.4 and her hgb dropped to 6.0 g/dL. Red blood cells were given along with FFP, vitamin K and a 2 nd dose of PCC. The patient continued to decline, was transferred to the ICU where she was intubated and placed on CRRT. Hematology was consulted for the persistently prolonged PT/INR in the setting of bleeding despite multiple interventions to correct the INR.The patient's last dose of apixaban was ~48 h prior to ICU admission. A rapid heparin anti-Xa assay was performed and upon comparison with an in-house nomogram the result, 1.78 IU/mL, correlated to an apixaban dose between 180-200 ng/ml (average peak levels 2-4 h after administration are 171 ng/mL). This result was confirmed the following day by an apixaban anti-Xa assay, 190 ng/mL. A repeat test performed 11 h later showed a minimal decrease in apixaban indicating impaired clearance.Therapeutic plasma exchange (TPE) was considered for rapid removal of apixaban. We performed a 1.0 plasma volume exchange, using plasma as the replacement fluid, to remove apixaban. Pre and post TPE drug levels were 172 and 108 ng/mL, respectively. Due to an elevated apixaban level the next day, a second TPE was performed which dropped the level to 87 ng/mL. The patient began to improve clinically, with hgb stabilization ~10 g/dL. She was extubated and transferred to a medical floor for further management. Apixaban levels were still measurable, 16 ng/mL, on post op day 8, 11 days after her last dose.Discussion:Apixaban is a highly protein-bound drug (~90%) that is rapidly absorbed in the small intestine with a large Vd (21 L) and a t1/2 of ~12 h. Elimination primarily occurs through the fecal route (Byon et al. 2019). The factors impairing the elimination of the drug in this patient were the following: 1. Pre-op constipation resulting in 10 days without a bowel movement; 2. Minimal bowel function post-op; and 3. Renal failure requiring CRRT after admission to the ICU.This case illustrates the profound effect intestinal obstruction/dysfunction can have on apixaban clearance. It also highlights the importance of laboratory test interpretation when managing coagulopathic patients. TPE is an effective way to remove drugs with high protein binding affinity (Mahmoud et al. 2021). TPE significantly reduced apixaban levels in our patient allowing for hemostasis and clinical improvement. To our knowledge, there are only two case reports regarding the effect of TPE on DOACs, one for apixaban, the other rivaroxaban (Hodulik et al. 2019).Conclusion:TPE can be considered as an option for rapid clearance of apixaban, or other highly protein bound anti-Xa inhibitors, in the setting of delayed elimination or when specific reversal agents are not safe/available. DisclosuresNo relevant conflicts of interest to declare.

Evaluation of the prothrombotic potential of four-factor prothrombin complex concentrate (4F-PCC) in animal models.

ObjectivesAcquired coagulopathy may be associated with bleeding risk. Approaches to restore haemostasis include administration of coagulation factor concentrates, but there are concerns regarding potential prothrombotic risk. The present study assessed the prothrombotic potential of four-factor prothrombin complex concentrate (4F-PCC) versus activated PCC (aPCC) and recombinant factor VIIa (rFVIIa), using three preclinical animal models.MethodsThe first model was a modified Wessler model of venous stasis-induced thrombosis in rabbit, focusing on dilutional coagulopathy; the second model employed the same system but focused on direct oral anticoagulant reversal (i.e. edoxaban). The third model assessed the prothrombotic impact of 4F-PCC, aPCC and rFVIIa in a rat model of ferric chloride-induced arterial thrombosis.ResultsIn the first model, thrombi were observed at aPCC doses ≥10 IU/kg (therapeutic dose 100 IU/kg) and rFVIIa doses ≥50 μg/kg (therapeutic dose 90 μg/kg), but not 4F-PCC 50 IU/kg (therapeutic dose 50 IU/kg). The impact of 4F-PCC (up to 300 IU/kg) on thrombus formation was evident from 10 minutes post-administration, but not at 24 hours post-administration; this did not change with addition of tranexamic acid and/or fibrinogen concentrate. 4F-PCC-induced thrombus formation was lower after haemodilution versus non-haemodilution. In the second model, no prothrombotic effect was confirmed at 4F-PCC 50 IU/kg. The third model showed lower incidence of thrombus formation for 4F-PCC 50 IU/kg versus aPCC (50 U/kg) and rFVIIa (90 μg/kg).ConclusionsThese results suggest that 4F-PCC has a low thrombotic potential versus aPCC or rFVIIa, supporting the clinical use of 4F-PCC for the treatment of coagulopathy-mediated bleeding.

Impact of Idarucizumab and Andexanet Alfa on DOAC Plasma Concentration and ClotPro® Clotting Time: An Ex Vivo Spiking Study in A Cohort of Trauma Patients.

Specific antagonists have been developed for the reversal of direct oral anticoagulants (DOAC). We investigated the impact of these reversal agents on the plasma concentration and visco-elastic test results of dabigatran and factor Xa inhibitors. After baseline measurements of dabigatran, the plasma concentration, and the visco-elastic ClotPro® ecarin clotting time (ECA-CT), we added the reversal agent Idarucizumab in vitro and these two analyses were repeated. Likewise, the baseline plasma concentration of apixaban, edoxaban, and rivaroxaban as well as ClotPro® Russell’s viper venom test clotting time (RVV-CT) were measured and reanalyzed following Andexanet alfa spiking. We analyzed fifty blood samples from 37 patients and 10 healthy volunteers. Idarucizumab decreased the measured dabigatran plasma concentration from 323.9 ± 185.4 ng/mL to 5.9 ± 2.3 ng/mL and ECA-CT from 706.2 ± 344.6 s to 70.6 ± 20.2 s, (all, p < 0.001). Andexanet alfa decreased the apixaban concentration from 165.1 ± 65.5 ng/mL to 9.8 ± 8.1 ng/mL, edoxaban from 152.4 ± 79.0 ng/mL to 36.4 ± 19.2 ng/mL, and rivaroxaban from 153.2 ± 111.8 ng/mL to 18.1 ± 9.1 ng/mL (all p < 0.001). Andexanet alfa shortened the RVV-CT of patients with apixaban from 239.2 ± 71.7 s to 151.1 ± 30.2 s, edoxaban from 288.2 ± 65.0 s to 122.7 ± 37.1 s, and rivaroxaban from 225.9 ± 49.3 s to 103.7 ± 12.1 s (all p < 0.001). In vitro spiking of dabigatran-containing blood with Idarucizumab substantially reduced the plasma concentration and ecarin-test clotting time. Andexanet alfa lowered the concentration of the investigated factor Xa-inhibitors but did not normalize the RVV-CT. In healthy volunteers’ blood, Idarucizumab spiking had no impact on ECA-CT. Andexanet alfa spiking of non-anticoagulated blood prolonged RVV-CT (p = 0.001), potentially as a consequence of a competitive antagonism with human factor Xa.

Implementation and Impact of a Multidisciplinary Coagulation Factor Stewardship Program

Introduction: Coagulation factor products are costly and can cause adverse outcomes when used inappropriately. Active stewardship may reduce the risk of inappropriate use, increase the likelihood of safe and effective use, and help control costs. Such goals may be met when these products are dispensed from an inpatient pharmacy. After multidisciplinary discussions of unmet clinical needs and pharmacoeconomic concerns, coagulation factor product guidelines for use were established at our institution and a multidisciplinary stewardship program was implemented.Objective: The purpose of this quality improvement initiative was to implement a multidisciplinary coagulation factor stewardship program and ascertain its impact on the use of coagulation factor products after dispensing them from inpatient pharmacy instead of the blood bank.Methods: We compared the utilization of 4-Factor prothrombin complex concentrate (4F-PCC) and recombinant factor VIIa (rVIIa) from the period of 7/1/16 to 5/31/17, 6 months prior to and 6 months after implementation of the stewardship program. Prior to implementation, pharmacists, hematologists, surgeons, anesthesiologists, and intensivists met to develop hospital-wide guidelines and order sets for 4F-PCC and rVIIa. The guidelines include indications for which 4F-PCC can be dispensed without hematology consultation and the requirement for hematology consultation for approval of requests outside of these guidelines. The Pharmacy & Therapeutics Committee approved all guidelines, order sets and the hematology service stewardship. Data about approval, administration, cost, and outcomes were obtained retrospectively for the 6 months prior and prospectively for the 6 months after implementation of the stewardship program.Results: Pre-implementation, 30 patients received 4F-PCC and 7 received rFVIIa. Warfarin reversal prior to emergent surgery (n=18, 60%) was the most common indication for 4F-PCC, followed by warfarin reversal for major bleeding (n=9, 30%) and direct oral anticoagulant (DOAC) reversal (n=3, 10%). Vitamin K was administered to 78% of the patients requiring warfarin reversal. The indications for rFVIIa included FVII deficiency (n=3, 42%), hemophilia with inhibitors (n=2, 29%), and refractory major bleeding (n=2, 29%). Of all patients, 7 (19%) died before discharge, but not within 72 hours and 1 (3%) had a thrombotic event within 72 hours. The cost of 4F-PCC and rFVIIa during the 6 months preceding the stewardship program was $261,880.After stewardship was implemented, 34 patients received 4F-PCC and 3 received rFVIIa. Indications for 4F-PCC included warfarin reversal prior to emergent surgery (n=21, 62%), warfarin reversal for major bleeding (n=5, 15%), DOAC reversal (n=4, 12%), and peri-operative management of other coagulopathies (n=4, 12%). Vitamin K was administered to 88% of patients requiring warfarin reversal. The pharmacy dispensed the products according to institutional guidelines in 88% of cases, and without hematology consultation when it should have been obtained in 12% of cases. Hematology was consulted for stewardship in 6 cases; 2 were approved and 4 were denied for disseminated intravascular coagulation (DIC) (n=2), factor V deficiency without active bleeding (n=1), and surgical bleeding (n=1). Of all patients, 10 (24%) died before discharge, including the 2 with DIC who were denied product. Three (7%) died within 72 hours and 2 (5%) had thrombotic events within 72 hours. The cost for 4F-PCC and rFVIIa was $160,144 after stewardship was implemented.Conclusions: Dispensing 4F-PCC and rFVIIa from the inpatient pharmacy with stewardship has resulted in similar utilization and efficacy as existed in the pre-implementation period but with cost savings of $101,000 during the first 6 months of stewardship. Furthermore, implementation of a multidisciplinary coagulation factor stewardship program with standardized institutional guidelines, streamlined dispensing from the inpatient pharmacy, as well as use of expert hematologic consultation when indicated, has enhanced the culture of safety in our institution. The experience has also enriched the training of hematology fellows, residents and pharmacists. DisclosuresFongemie:Bristol Myers Squibb: Speakers Bureau. Comenzo:Janssen: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Karyopharm: Research Funding.

The Use of 4F-PCC to Correct Direct Oral Anticoagulant (DOAC)-Induced Coagulopathy: An Observational Analysis

IntroductionWith the approval of four-factor prothrombin complex concentrate (4F-PCC, Kcentra) for the reversal of vitamin K antagonist-associated bleeding in the US, it has become a relatively common practice for 4F-PCC to be used in an ‘off-label’ fashion to correct coagulopathy caused by direct oral anticoagulants (DOACs) such as anti-Xa inhibitors. However, the efficacy and safety of 4F-PCC have not been well-studied in this scenario.MethodsWe performed a retrospective observational study on the off-label use of 4F-PCC for reversing DOAC-associated bleeding in a level one trauma center between November 2014 and February 2017; this time frame reflects the earliest time of using 4F-PCC as part of a DOAC reversal protocol at our facility. Data collected from the electronic medical record included: age, gender, and weight of patients, indications and dosage of 4F-PCC, INR as well as hemoglobin (Hgb) prior to and post 4F-PCC administration, clinical outcomes, and acute and chronic thromboembolic events occurring within 24 hours and 45 days of 4F-PCC administration respectively. In addition, thromboembolic events (if documented by primary teams) post 4F-PCC infusions were subsequently evaluated by both authors to determine the potential contributions of 4F-PCC.ResultsWe identified 25 patients on DOACs who received 4F-PCC in our center during the study time frame. The patients included 14 females and 11 males with an average age of 68.27 ±17.46 years old. DOACs were essentially used in these patients for either atrial fibrillation (n=19) or prophylaxis for deep venous thrombosis /pulmonary embolism (n=6). Specifically, 13 patients were on Apixiaban, 11 on Rivaroxaban, and one on Fondaparinux. 4F-PCC was used to reverse DOAC-induced coagulopathy in the context of acute life-threatening bleeding and urgent surgeries /invasive procedures. The most common indications for 4F-PCC in our patients were intracranial hemorrhage (ICH; n=13), and gastrointestinal (GI) bleeding (n=8). Others were emergent surgeries (n=2), retroperitoneal hematoma (n=1) and vaginal bleeding (n=1). All except one patient (24/25 patients) received one dose of 4F-PCC; dosages of 4F-PCC were as follows: 50 U/Kg for 20 patients, 25 U/Kg for five patients and undocumented for one patient. Patients on DOACs did not show a significant decrease of INR after 4F-PCC administration (average pre-INR=1.13±0.21, average post-INR =1.03±0.05, p=0.06). However, clinically 4F-PCC appeared effective in stopping DOAC-associated bleeding. The bleeding of most patients (20/25 patients) improved as demonstrated by stabilized intracranial hemorrhage sizes and/or by steady Hgb concentrations (average Hgb concentration change = 0.13 ±1.94mg/dL, or average Hgb percentage change=3.22±23% of pre-Hgb concentration). Of note, some patients received RBC transfusions as well, thus the post-Hgb values were the combination results of 4F-PCC and RBC administrations. Notably, five patients died within one week of their bleeds/4F-PCC administration: four due to ICH and one due to GI bleeding. The cause of death for the four patients with ICH was attributable in all cases to irreversible brain damage associated with the initial hemorrhage (this despite the fact that bleeding was apparently controlled in all of these cases as per stabilization of hemorrhage size by imaging). The patient with massive GI bleeding died from intolerance to surgical intervention. In addition, we found 4F-PCC as associated with no thromboembolic events during the first 24 hours after 4F-PCCadministration. During 2-45 days post-4F-PCC infusion, four patients (4/25=16%) were found to have thromboembolic events: stroke, myocardial infarct, atrial thrombi and non-occlusive IJ tube thrombi.ConclusionsOur data showed that 4F-PCC was relatively efficient in aiding the ‘reversal’ of DOACs for patients with severe hemorrhage. We did notice that 16% of patients experienced some form of thromboembolic events in the days-to-weeks after 4F-PCC administration, although the imputability of 4F-PCC in these processes (versus their underlying disease) is difficult to parse out. Additional, prospective studies would be warranted to further evaluate the safety of 4F-PCC for this off-label indication. DisclosuresNo relevant conflicts of interest to declare.

Direct oral anticoagulant reversal: An update.

The rise in direct oral anticoagulant (DOAC) use means nurses must understand the reversal of these agents in case of bleeding. Depending on bleed severity, as well as other criteria, pharmacologic reversal can be considered in place of supportive care alone. Knowledge of literature surrounding DOAC reversal is crucial.

2021 Update of the International Council for Standardization in Haematology Recommendations for Laboratory Measurement of Direct Oral Anticoagulants.

In 2018, the International Council for Standardization in Haematology (ICSH) published a consensus document providing guidance for laboratories on measuring direct oral anticoagulants (DOACs). Since that publication, several significant changes related to DOACs have occurred, including the approval of a new DOAC by the Food and Drug Administration, betrixaban, and a specific DOAC reversal agent intended for use when the reversal of anticoagulation with apixaban or rivaroxaban is needed due to life-threatening or uncontrolled bleeding, andexanet alfa. In addition, this ICSH Working Party recognized areas where additional information was warranted, including patient population considerations and updates in point-of-care testing. The information in this manuscript supplements our previous ICSH DOAC laboratory guidance document. The recommendations provided are based on (1) information from peer-reviewed publications about laboratory measurement of DOACs, (2) contributing author's personal experience/expert opinion and (3) good laboratory practice.