Anticoagulant-associated Bleeding Research Articles

Long-Term Safety of a Four-Factor Prothrombin Complex Concentrate (Kcentra®/Beriplex® P/N): An Updated Pharmacovigilance Review.

Four-factor prothrombin complex concentrate (4F-PCC) is recommended for vitamin K antagonist reversal in patients with major bleeding or in need of surgery. The most important risk associated with the use of 4F-PCC is the occurrence of thromboembolic events (TEEs). In this review, we aim to evaluate the safety profile of a 4F-PCC (Kcentra®/Beriplex® P/N; CSL Behring, Marburg, Germany) by reviewing pharmacovigilance data. A retrospective analysis of postmarketing pharmacovigilance data of Kcentra®/Beriplex® P/N from February 1996 to April 2022 was performed and complemented by a review of clinical studies published between January 2012 and April 2022. A total of 2,321,443 standard infusions of Kcentra®/Beriplex® P/N were administered during the evaluation period. Adverse drug reactions (ADRs) were reported in 614 cases (∼1 per 3,781 standard infusions) and 233 of these cases (37.9%) experienced suspected TEEs related to 4F-PCC (∼1 per 9,963 standard infusions); most of these cases had pre-existing or concomitant conditions likely to be significant risk factors for thrombosis. TEE rates were similar when 4F-PCC was used on-label or off-label for direct oral anticoagulant-associated bleeding. Thirty-six cases (5.9%) reported hypersensitivity type reactions (∼1 per 64,485 standard infusions). No confirmed case of viral transmission related to 4F-PCC use was reported. The published literature also revealed a favorable safety profile of 4F-PCC. Analysis of postmarketing pharmacovigilance safety reports demonstrated that treatment with 4F-PCC was associated with few ADRs and a low rate of TEEs across multiple indications and settings, thus confirming a positive safety profile of 4F-PCC.

Engineering and evaluation of FXa bypassing agents that restore hemostasis following Apixaban associated bleeding

Direct oral anticoagulants (DOACs) targeting activated factor Xa (FXa) are used to prevent or treat thromboembolic disorders. DOACs reversibly bind to FXa and inhibit its enzymatic activity. However, DOAC treatment carries the risk of anticoagulant-associated bleeding. Currently, only one specific agent, andexanet alfa, is approved to reverse the anticoagulant effects of FXa-targeting DOACs (FXaDOACs) and control life-threatening bleeding. However, because of its mechanism of action, andexanet alfa requires a cumbersome dosing schedule, and its use is associated with the risk of thrombosis. Here, we present the computational design, engineering, and evaluation of FXa-variants that exhibit anticoagulation reversal activity in the presence of FXaDOACs. Our designs demonstrate low DOAC binding affinity, retain FXa-enzymatic activity and reduce the DOAC-associated bleeding by restoring hemostasis in mice treated with apixaban. Importantly, the FXaDOACs reversal agents we designed, unlike andexanet alfa, do not inhibit TFPI, and consequently, may have a safer thrombogenic profile.

Direct oral anticoagulant-associated bleeding complications in patients with gastrointestinal cancer and venous thromboembolism

BackgroundDirect oral anticoagulants (DOACs) have become widely used for cancer-associated venous thromboembolism (VTE). However, DOAC-associated bleeding complications remain challenging, especially in patients with gastrointestinal (GI) cancer. This study aimed to compare the bleeding outcomes between patients with upper or lower GI cancers and those without GI cancer. MethodsUsing the COMMAND VTE Registry-2 database, which is a multicenter registry enrolling 5197 consecutive acute symptomatic VTE patients among 31 centers in Japan between January 2015 and August 2020, we identified 1149 active cancer patients with DOACs (upper GI cancer: N = 88; lower GI cancer: N = 114; non-GI cancer: N = 947). The primary outcome was major bleeding during anticoagulation therapy, which was evaluated in the competing risk regression model. ResultsThe upper GI cancer group had a lower mean body weight, and most often had anemia. The cumulative 5-year incidence of major bleeding was higher in the upper GI cancer group (upper GI cancer: 22.4 %, lower GI cancer: 15.4 %, and non-GI cancer: 11.6 %, P = 0.015). The most frequent major bleeding site in the upper GI cancer group was the upper GI (53 %), followed by the lower GI (24 %). After adjusting for the confounders, the excess risk in upper GI cancer relative to non-GI cancer remained significant for major bleeding (adjusted subhazard ratio, 2.25; 95 %CI, 1.31–3.87, P = 0.003), but that in lower GI cancer was insignificant. ConclusionsUpper GI cancer, but not lower GI cancer, as compared to non-GI cancer was associated with a higher risk for major bleeding during anticoagulation therapy with DOACs.Clinical Trial Registration: URL: http://www.umin.ac.jp/ctr/index.htmUnique identifier: UMIN000044816.

Qualitative experiences, values, and decisional needs of patients with unprovoked venous thromboembolism who suffer bleeding—“This pill will keep you alive tonight”

BackgroundContemporary guidelines recommend extended-duration anticoagulation among patients with a first unprovoked venous thromboembolism (VTE). Little is known about whether this recommendation aligns with patient values after a bleeding complication. ObjectivesTo explore the experiences, values, and decisional needs of patients with unprovoked VTE related to extended-duration treatment after an anticoagulant-associated bleed. MethodsIn this descriptive, qualitative study, face to face online semistructured interviews were conducted with patients with unprovoked VTE who had experienced bleeding and continued anticoagulant treatment in one academic hospital in Canada. Data were analyzed using directed content analysis to identify themes. Themes were mapped onto the Ottawa Decisional Support Framework to identify decisional needs. ResultsBetween September and December 2021, 14 patients were interviewed (age 41-69 years; 9 females). Many patients were not aware of the option to stop anticoagulation and had limited understanding of the decision about treatment duration. Despite the negative quality-of-life impact of clinically relevant bleeding during VTE treatment, the majority continued anticoagulation due to emotional trauma of VTE diagnosis, a perception that bleeding would be more manageable than VTE recurrence, a desire to maintain a connection to subspecialty care or non-VTE related benefits (eg, cancer diagnosis, protection from COVID-19). Patients’ decisional needs included lack of choice awareness, inadequate support for participation, lack of personalized risk stratification, and inadequate information on monitoring and managing heavy menstrual bleeding. ConclusionDespite the impact of anticoagulant-associated bleeding on quality of life, patients preferred continuing with anticoagulation for reasons extending beyond secondary VTE prevention. Effective decision-support interventions are needed to address unmet decisional needs.

Do treatment methods for deep vein thrombosis have different effects on post-thrombotic syndrome and the quality of life?

This study aimed to compare the effects of interventional methods and medical therapy in patients with acute proximal deep vein thrombosis (DVT) on the risk of development of post-thrombotic syndrome (PTS) and the quality of life during the follow-up period. Clinical statuses of the patients who were treated medical therapy alone or medical therapy and endovascular treatment for acute proximal (iliofemoral-popliteal) DVT between 1st January 2014 and 1st November 2022 were reviewed retrospectively. The study included 128 patients who received interventional treatment (Group I) and 120 patients who received medical therapy alone (Group M). The mean age of the patients was 52.98 ± 12.45years in Group I and 55.60 ± 16.15years in Group M. Patients were classified as provoked or unprovoked and by LET scale (lower extremity thrombosis level scale). Patients were followed-up for 1year using Villalta scores and VEINES-QoL/Sym questionnaire. LET scale was evaluated based on the results of lower extremity venous Doppler ultrasound (DUS). No early acute phase mortality was observed. LET classification showed that there is higher proximal involvement in Group I (Table 1[Table: see text]). Recurrence rate was 6.25% (8 patients) in Group I and 21.66% (26 patients) in Group M (p < .001). Pulmonary embolism was not observed in either group. At 12-month follow-up, the number of patients with a Villalta score of ≥5 was 8 (6.25%) in Group I and 81 (67.5%) in Group M (p < .001), while the mean VEINES-QoL/Sym scale score was found to be 72.5 ± 6.35 in Group I and 40.2 ± 9.31 in Group M (p < .001). The rates of anticoagulant-associated bleeding were 3.12% (4 patients) in Group I and 6.66% (8 patients) in Group M. The mean complete recanalization rates calculated using DUS at year 1 was found to be 63.28% (81 patients) in Group I and 9.16% (11 patients) in Group M (p < .001). When deep vein thrombosis is treated using interventional methods, lower Villalta scores are detected after 1year of follow-up. Development of post-thrombotic syndrome is reduced substantially. According to VEINES-QoL/Sym quality of life (QoL) scale, QoL is higher in patients who underwent interventional procedures. Interventional treatment provides persistent benefit in the short and medium terms especially in DVT with proximal involvement.

Retrospective Analysis of the Real-World Utilization of 4-Factor Prothrombin Complex Concentrate and Plasma in Oral Anticoagulant-Associated Bleeding in US Hospitals.

Real-world utilization of 4-factor prothrombin complex concentrate (4F-PCC) and plasma for the management of oral anticoagulant (OAC)-associated bleeding in US trauma hospitals was described.This is amulticenter, retrospective chart review evaluating the use of 4F-PCC and plasma in OAC reversal across medical specialties. Physicians completed a survey and extracted data from 3 to 5 patient charts. Variables of interest included medical specialty, urgency, and bleed type. Two hundred and thirty-five physicians completed the survey, and 861 patient charts were included in the study. 4F-PCC was commonly used in life-threatening or emergent indications, whereas plasma was used in emergent and urgent indications. Plasma was used mostly for patients on warfarin (53% vs 47% 4F-PCC) and 4F-PCC for those on apixaban (82% vs 18% plasma) and rivaroxaban (77% vs 23% plasma). This retrospective analysis showed that 4F-PCC was predominantly used for OAC reversal despite available specific reversal agents for some of the OAC. Although it is not recommended by any reversal guidelines, plasma is still used for OAC reversal. Plasma should be avoided in the management of OAC-associated bleeding.

Thrombosis and anticoagulation: clinical issues of special importance to hematologists who practice in Asia

There are clinical issues of special importance and practice variation in the management of venous thromboembolism (VTE) and in the use of anticoagulants among hematologists who practice in Asia. In Asian-inherited thrombophilia, coagulation is disturbed due to loss-of-function mutations of protein S and protein C causing protein S and protein C deficiencies, whereas the gain-of-function factor V Leiden and prothrombin G20210A mutations are almost absent. Thrombophilia screening is not recommended in patients with VTE patients who have major provoking factors. However, it can be considered in unprovoked young patients with VTE who have a strong family history of VTE. Cancer is the most important acquired risk factor for VTE in Asians. Limited cancer screening at the initial presentation of unprovoked VTE is appropriate, especially in the elderly. Direct oral anticoagulants have been shown to have similar efficacy and reduce risk of major bleeding, including intracranial hemorrhage and bleeding requiring hospitalization, compared with warfarin. Most clinical trials evaluating therapies for treatment and prevention of VTE have included small numbers of Asian patients. Despite this lack of evidence, direct oral anticoagulants have been increasingly used in Asia for cancer-associated thrombosis. Individualized assessment of thrombotic and bleeding risks should be used for all hospitalized Asian patients when deciding on pharmacologic thromboprophylaxis. More research is needed to understand the factors that contribute to risks of VTE and anticoagulant-associated bleeding in Asian patients as these may differ from Western populations.

Risk of Intracranial Hemorrhage with Direct Oral Anticoagulants (DOACs) Versus Low Molecular Weight Heparin (LMWH) in Primary and Secondary Brain Cancers: An up-to-Date Meta-Analysis of Comparative Studies

Introduction Patients with brain tumors, primary or metastatic, are at high risk for thromboembolic events and anticoagulant-associated bleeding. LMWH has been the standard treatment for many years. Recently, DOACs are more frequently used in cancer patients. However, such patient populations have been under-represented in anticoagulation trials. As such, there continues to be concerns regarding their safety in patients with primary and metastatic brain cancers especially with respect to intracranial hemorrhages (ICH). There are no trials in brain cancers comparing the safety of DOACs to LMWH in a head-to-head manner. This meta-analysis was conducted to compare the relative risk (RR) of ICH of DOACs to that of LMWH in patients with brain cancers. Methods A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language, diagnosis of primary brain cancers (PBC) or metastatic brain cancers (MBC), comparative studies using anticoagulation with LMWH versus DOACs, and studies that reported the incidence of ICH. A meta-analysis using the fixed effects and random effects models was conducted. Results Four retrospective comparative studies with a total of 488 patients were included. Three studies reported on ICH incidence of DOACs versus LMWH in PBC and MBC separately and one reported on ICH incidence in MBC only. DOACs were found to have significantly lower RR of all types of ICH in patients with PBC (RR=0.18, 95%CI 0.05-0.62) and a borderline significant lower RR in MBC (RR=0.66, 95%CI 0.41-1.08) than LMWH. However, there was no significant difference between DOACs and LMWH with respect to major ICH in patients with MBC. Conclusions This is the first meta-analysis to show that DOACs is associated with lower relative risk of all ICH compared to LMWH in patients with primary and metastatic brain cancers. In the absence of randomized clinical trials, it represents the most compelling data supporting the use of DOACs to treat thromboembolic events in these patient populations.

Factor XI Inhibition for the Prevention of Venous Thromboembolism: An Update on Current Evidence and Future perspectives

During the past decade, emergence of direct oral anticoagulants (DOACs) has drastically improved the prevention of thrombosis. However, several unmet needs prevail in the field of thrombosis prevention, even in the DOACs’ era. The use of DOACs is still constrained and the drugs cannot be administered in every clinical scenario, such as an increased anticoagulant-associated bleeding risk, particularly in some specific populations (cancer – notably those with gastrointestinal or genitourinary cancer – and frail patients), the impossibility to be used in certain patients (eg, end-stage kidney failure during hemodialysis, pregnancy and breastfeeding), and their lack of efficacy in certain clinical scenarios (eg, mechanical heart valves, triple-positive antiphospholipid syndrome). Efforts to find a factor that upon antagonization prevents thrombosis but spares haemostasis have resulted in the identification of coagulation factor XI (FXI) as a therapeutic target. After briefly recapitulating the role of factor XI in the balance of haemostasis, we propose a narrative review of the key data published to date with compounds targeting factor XI to prevent thrombosis as well as the main ongoing clinical studies, opening up prospects for improving the care of patients requiring thrombosis prevention.

In Search of the Appropriate Anticoagulant-Associated Bleeding Risk Assessment Model for Cancer-Associated Thrombosis Patients.

Simple SummaryPatients with venous thromboembolism events in the context of cancer should receive anticoagulants as long as the cancer is active. Therefore, a tailor-made anticoagulation strategy should rely on an individualized assessment of the risks of recurrent venous thromboembolism and anticoagulant-associated bleeding. No existing risk assessment model for anticoagulant-associated bleeding risk has been validated for cancer-associated thrombosis. To obtain a better risk assessment model to assess anticoagulant-associated bleeding risk in cancer-associated thrombosis patients, we deemed it necessary to answer questions related to how and when to assess anticoagulant-associated bleeding risk as well as what factors to assess for which patients. Patients with venous thromboembolism events (VTE) in the context of cancer should receive anticoagulants as long as the cancer is active. Therefore, a tailor-made anticoagulation strategy should rely on an individualized risk assessment model (RAM) of recurrent VTE and anticoagulant-associated bleeding. The aim of this review is to investigate the applicability of the currently available RAMs for anticoagulant-associated bleeding after VTE in the CAT population and to provide new insights on how we can succeed in developing a new anticoagulant-associated bleeding RAM for the current medical care of CAT patients. A systematic search for peer-reviewed publications was performed in PubMed. Studies, including systematic reviews, were eligible if they comprised patients with VTE and used a design for developing a prediction model, score, or other prognostic tools for anticoagulant-associated bleeding during anticoagulant treatment. Out of 15 RAMs, just the CAT-BLEED was developed for CAT patients and none of the presented RAMs developed for the VTE general population were externally validated in a population of CAT patients. The current review illustrates the limitations of the available RAMs for anticoagulant-associated bleeding in CAT patients. The development of a RAM for bleeding risk assessment in patients with CAT is warranted.

Activated prothrombin complex concentrates for direct oral anticoagulant-associated bleeding or urgent surgery: Hemostatic and thrombotic outcomes

IntroductionStudies evaluating the use of activated prothrombin complex concentrates (aPCCs) for DOAC-associated bleeding are sparse. Materials and methodsWe conducted a retrospective study of patients receiving aPCC for DOAC-associated bleeding or for pre-operative optimization of hemostasis prior to urgent surgery. The primary efficacy outcome was hemostatic efficacy, the primary safety outcome was the 30-day thromboembolic complication rate. ResultsEighty-two patients were included in the analysis; 14 patients on dabigatran, 39 patients on rivaroxaban and 29 patients on apixaban. Fifty-four patients received aPCC for major bleeding and 28 patients prior to urgent surgery. Mean aPCC dosing was 2974 IU (SD ± 857 IU). Hemostasis was deemed effective by ISTH criteria in 50% of cases and “Good” or “Moderate” by Sarode criteria in 45.2% and 14.3% of cases, respectively. Surgical hemostasis was rated as “Normal” in 84% of cases pre-operative administration. Median pre-aPCC INR was 1.6 (IQR 0.5) and median post-aPCC INR was 1.2 (IQR 0.2) (p < 0.00001). Median pre-aPCC aPTT was 36 s (IQR 12.8), median post-aPCC aPTT was 29 s (IQR 9.8) (p = 0.0001). The 30-day thromboembolic event rate was 6.1%. ConclusionFurther study is needed to characterize the hemostatic effects and thromboembolic risk of aPCC among patients with DOAC-associated bleeding or for attempted normalization of hemostasis prior to urgent surgery.

LO94: Evaluation of stroke and bleeding outcomes among patients managed in the emergency department for newly diagnosed atrial fibrillation

Introduction: Atrial Fibrillation (AF) is the most common arrhythmia seen in patients presenting to the emergency department (ED). AF increases the risk of ischemic stroke which can be mitigated by anticoagulant prescription. National guidelines advise that emergency physicians initiate anticoagulation when AF is first diagnosed. We aimed to evaluate the 90-day incidence of stroke and major bleeding among emergency patients discharged home with a new diagnosis of AF. Methods: This was a health records review of patients diagnosed with AF in two EDs. We included patients ≥ age 18, with a new diagnosis of AF who were discharged from the ED, between 1st May 2014 and 1st May 2017. Using a structure review we collected data on CHADS65 and CHADS2 scores, contraindications to direct oral anticoagulant (DOAC) prescription and initiation of anticoagulation in the ED. Patient charts were reviewed for the diagnosis of stroke, transient ischemic attack (TIA), ischemic gut, ischemic limb or other systemic embolism within 90 days of the index ED presentation. We extracted data on major bleeding events within 90 days, defined by the International Society of Thrombosis and Haemostasis criteria. All data were extracted in duplicate for validation. Results: We identified 399 patients fulfilling the inclusion criteria, median age 68 (IQR 57-79), 213 (53%) male. 11 patients were already prescribed an anticoagulant for another indication and 19 had a contraindication to prescription of a DOAC. 48/299 (16%) CHADS65 positive patients were initiated on an anticoagulant, 3 of whom had a contra-indication to initiation of anticoagulation in the ED (1 dual antiplatelet therapy, 2 liver cirrhosis). 1/100 CHADS65 negative patients was initiated on anticoagulation. The median CHADS2 score was 1 (IQR 0-2). Among the 49 patients initiated on anticoagulation, 3 patients had a stroke/TIA within 90 days, 6.1% (95% CI; 2.1-16.5%). There were no bleeding events 0.0% (95% CI; 0.0-7.3%). Among the 350 patients who were not initiated on anticoagulation in the ED, 4 patients had a stroke/TIA 1.1% (95% CI; 1.1-2.9%) within 90 days and 2 patients had a major bleeding event. Conclusion: Prescription of anticoagulation for new diagnoses of AF was under-utilized in these EDs. The 90-day stroke/TIA rate was high, even among those given an anticoagulant prescription in the ED. No patient had an anticoagulant-associated bleeding event.

Management of Severe Bleeding in Patients Treated With Oral Anticoagulants: Proceedings Monograph From the Emergency Medicine Cardiac Research and Education Group-International Multidisciplinary Severe Bleeding Consensus Panel October 20, 2018.

In this Emergency Medicine Cardiac Research and Education Group (EMCREG)-International Proceedings Monograph from the October 20, 2018, EMCREG-International Multidisciplinary Consensus Panel on Management of Severe Bleeding in Patients Treated With Oral Anticoagulants held in Orlando, FL, you will find a detailed discussion regarding the treatment of patients requiring anticoagulation and the reversal of anticoagulation for patients with severe bleeding. For emergency physicians, critical care physicians, hospitalists, cardiologists, internists, surgeons, and family physicians, the current approach and disease indications for treatment with anticoagulants such as coumadin, factor IIa, and factor Xa inhibitors are particularly relevant. When a patient treated with anticoagulants presents to the emergency department, intensive care unit, or operating room with severe, uncontrollable bleeding, achieving rapid, controlled hemostasis is critically important to save the patient's life. This EMCREG-International Proceedings Monograph contains multiple sections reflecting critical input from experts in Emergency Cardiovascular Care, Prehospital Emergency Medical Services, Emergency Medicine Operations, Hematology, Hospital Medicine, Neurocritical Care, Cardiovascular Critical Care, Cardiac Electrophysiology, Cardiology, Trauma and Acute Care Surgery, and Pharmacy. The first section provides a description of the current indications for the treatment of patients using oral anticoagulants including coumadin, the factor IIa (thrombin) inhibitor dabigatran, and factor Xa inhibitors such as apixaban and rivaroxaban. In the remaining sections, the treatment of patients presenting to the hospital with major bleeding becomes the focus. The replacement of blood components including red blood cells, platelets, and clotting factors is the critically important initial treatment for these individuals. Reversing the anticoagulated state is also necessary. For patients treated with coumadin, infusion of vitamin K helps to initiate the process of protein synthesis for the vitamin K-dependent coagulation proteins II, VII, IX, and X and the antithrombotic protein C and protein S. Repletion of clotting factors for the patient with 4-factor prothrombin complex concentrate, which includes factors II (prothrombin), VII, IX, and X and therapeutically effective concentrations of the regulatory proteins (protein C and S), provides real-time ability to slow bleeding. For patients treated with the thrombin inhibitor dabigatran, treatment using the highly specific, antibody-derived idarucizumab has been demonstrated to reverse the hypocoagulable state of the patient to allow blood clotting. In May 2018, andexanet alfa was approved by the US Food and Drug Administration to reverse the factor Xa anticoagulants apixaban and rivaroxaban in patients with major bleeding. Before the availability of this highly specific agent, therapy for patients treated with factor Xa inhibitors presenting with severe bleeding usually included replacement of lost blood components including red blood cells, platelets, and clotting factors and 4-factor prothrombin complex concentrate, or if not available, fresh frozen plasma. The evaluation and treatment of the patient with severe bleeding as a complication of oral anticoagulant therapy are discussed from the viewpoint of the emergency physician, neurocritical and cardiovascular critical care intensivist, hematologist, trauma and acute care surgeon, hospitalist, cardiologist, electrophysiologist, and pharmacist in an approach we hope that the reader will find extremely practical and clinically useful. The clinician learner will also find the discussion of the resumption of oral anticoagulation for the patient with severe bleeding after effective treatment important because returning the patient to an anticoagulated state as soon as feasible and safe prevents thrombotic complications. Finally, an EMCREG-International Severe Bleeding Consensus Panel algorithm for the approach to management of patients with life-threatening oral anticoagulant-associated bleeding is provided for the clinician and can be expanded in size for use in a treatment area such as the emergency department or critical care unit.

Healthcare resource utilization and costs among patients with direct oral anticoagulant or warfarin-related major bleeding

IntroductionDirect oral anticoagulants (DOACs) have expanded the options for antithrombotic therapy. DOAC-related major bleeds are associated with favorable outcomes compared to warfarin in clinical trials and routine practice. However, it is unclear whether management of DOAC-associated major bleeding incurs higher resource utilization and costs. Materials and methodsWe screened medical records of patients ≥ 66 years with atrial fibrillation admitted to one of five tertiary care hospitals in Ontario, Canada with a hemorrhage. We abstracted bleeds involving DOACs or warfarin and linked them to administrative databases to capture length of hospital stay, blood product use, procedural interventions, intensive care unit (ICU) utilization and related direct medical costs. To control for confounders, multivariate logistic and linear regressions were used for binary and linear outcomes respectively. ResultsAmong 19,061 records screened, 1978 (10.4%) cases involving 1632 patients met criteria of oral anticoagulant-associated bleeding. Baseline characteristics between DOAC and warfarin groups were similar. Blood product costs were higher for DOACs (all comparisons DOACs vs. warfarin, $1456 vs. $1109, mean difference $347, 95% CI $185 to $509), but length of stay and ICU use were similar. Mean direct medical costs did not differ ($9217 vs. $10,790, adjusted relative ratio 0.94, 95% CI 0.84–1.05). ConclusionsPrior to introduction of DOAC-specific reversal agents, resource utilization and medical costs were comparable between DOAC- and warfarin-associated major bleeds, despite marginally higher blood product costs incurred by the former. Resource intensity associated with anticoagulant-related bleeding remains high, and our data provide measures for cost-effectiveness evaluation of emerging DOAC antidotes.

Outcomes of Direct Oral Anticoagulant- and Warfarin-Associated Hemorrhage: A Single Center Retrospective Cohort Study

Background:Direct oral anticoagulants (DOAC) are now a mainstay of anticoagulant therapy. However, outside of clinical trials, reports on treatment of DOAC-related bleeding are limited. We report a retrospective cohort study of the management and outcomes of oral anticoagulant-associated bleeding in a single medical center in the United States.Methods: Patients ≥ 18 years admitted to one of four Emory Hospitals for bleeding while taking warfarin or DOAC (rivaroxaban, apixaban, edoxaban, or dabigatran) for atrial fibrillation, atrial flutter, or venous thromboembolism between October 2010 and June 2017 were identified using ICD9-10 codes from the clinical data warehouse (CDW). Patients were excluded if they had additional cardiac indications for warfarin, in-hospital or peri-procedural bleeding, admitted with ICD codes for abnormal coagulation without bleeding, or were transferred from another hospital. For patients with multiple admissions, only the initial bleeding episode was included. Patient characteristics, bleeding site, treatment, and outcome (length of stay [LOS] or death) were obtained from the CDW. Data from a random sample (20% of patients) was verified through chart review demonstrating that the ICD codes for bleeding have a positive predictive value of 94.7%. Death events were confirmed using the National Death Index. Data was summarized and compared between groups (DOAC vs warfarin) using standardized differences and Fisher exact test. Poisson regression was used to calculate risk ratios in the use of blood products and reversal agents, and in-hospital and 30-day mortality.Results:Of the 277 patients included in the data abstraction and analysis, 89 (32.1%) received a DOAC and 188 (67.8%) received warfarin. The mean age was similar between groups (DOAC 76.4 years vs warfarin 73.6 years). Patients in the DOAC group compared to the warfarin group were more likely to be of white (70.8% vs 50.5%) vs African American race (24.7% vs 44.1%). The ISTH criterion for major bleed was met by 47 (52.8%) and 108 (57.4%) in the DOAC and warfarin groups, respectively. Within the DOAC group, most were on rivaroxaban (60.7%). Patients taking warfarin compared to DOAC were more likely to have a Charlson Comorbidity Index (CCI) of 2+ (63.9% vs 49.4%). There was no significant difference in bleeding sites between groups. Gastrointestinal was the most common site of bleeding in both groups (80.9% DOAC, 71.3% warfarin). Intracranial hemorrhage was reported in 12.4% of DOAC and 8.5% of warfarin group.Patients in the warfarin group were more likely to receive a blood product during hospitalization for anticoagulation-related bleeding event compared to those receiving DOACs (66.5% vs 46.1%, adjusted RR 0.68 [95% CI 0.47, 0.97], Table 1). The difference is mainly driven by the higher rate of FFP administration in the warfarin group. As expected, vitamin K use was also higher in the warfarin group compared to the DOAC group. Utilization of non-activated PCC was low in both DOAC (6.7%) and warfarin (3.7%) groups without statistically significant difference. Of 17 patients on dabigatran, 4 (23.5%) were admitted after FDA approval of idarucizumab; 2/4 had a major bleed but idarucizumab was not used.In-hospital death (Table 2) occurred in 5.6% of patients in the DOAC group compared with 2.1% in the warfarin group. The Kaplan-Meier curve (Figure 1) showed a trend for higher survival probability in warfarin-related bleeding event compared to DOAC (P=0.052). However, in-hospital and 30-day mortality were not statistically significantly different between groups after adjustment for age, race, and CCI (Table 2). There was no significant difference in median hospital LOS (3.19 days DOAC vs 3.97 days warfarin).Conclusions:We report experience of anticoagulant-related hemorrhage in a large metropolitan healthcare system. Despite > 50% with major bleeding and lack of specific antidote for DOAC, we found an overall low in-hospital mortality and short LOS which was not significantly different between DOAC or warfarin users. Total blood product administration was higher in warfarin compared to DOAC-related bleeding. Hemostatic or reversal agents were rarely, if ever used, for management of DOAC-related bleeding. This study highlights that as the complexity of anticoagulants and their reversal increases, the need to optimize hospital systems for anticoagulation reversal strategies also increases. DisclosuresKempton:Novo Nordisk: Research Funding; Genetech, Inc: Honoraria, Research Funding; Shire: Honoraria; Bayer AG: Honoraria; Spark Therapeutics: Honoraria; Grifols: Honoraria; Catalyst Biosciences: Honoraria.

Comparison of reversal activity and mechanism of action of UHRA, andexanet, and PER977 on heparin and oral FXa inhibitors

AbstractAnticoagulants such as unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and direct oral anticoagulants (DOACs) targeting thrombin (IIa) or factor Xa (FXa) are widely used in prevention and treatment of thromboembolic disorders. However, anticoagulant-associated bleeding is a concern that demands monitoring and neutralization. Protamine, the UFH antidote, has limitations, while there is no antidote available for certain direct FXa inhibitors. Improved antidotes in development include UHRA (Universal Heparin Reversal Agent) for all heparin anticoagulants; andexanet alfa (andexanet), a recombinant antidote for both direct FXa inhibitors and LMWHs; and ciraparantag (PER977), a small-molecule antidote for UFH, LMWHs, and certain DOACs. The binding affinities of these antidotes for their presumed anticoagulant targets have not been compared. Here, isothermal titration calorimetry (ITC) was used to determine the affinity of each antidote for its putative targets. Clotting and chromogenic FXa assays were used to characterize neutralization activity, and electron microscopy was used to visualize the effect of each antidote on clot morphology in the absence or presence of anticoagulant. ITC confirmed binding of UHRA to all heparins, and binding of andexanet to edoxaban and rivaroxaban, and to the antithrombin–enoxaparin complex. PER977 was found to bind heparins weakly, but not the direct FXa inhibitors studied. For UHRA and andexanet, an affinity at or below the micromolar level was found to correlate with neutralization activity, while no reversal activity was observed for the PER977/anticoagulant systems. Standard metrics of clot structure were found to correlate weakly with PER977's activity. This is the first study comparing 3 antidotes in development, with each exerting activity through a distinct mechanism.

How I manage patients with anticoagulation-associated bleeding or urgent surgery.

Antithrombotic treatment puts patients at risk of major bleeding. Fast and adequate response to anticoagulant-associated bleeding may not only stop the bleeding but prevent severe complications. However, practical treatment algorithms to guide physicians in emergency situations are lacking. Important principles that arise from management of bleeding in general are (a) implementation of an in-house algorithm, (b) rapid identification and treatment of the bleeding source, (c) adequate fluid resuscitation, (d) consideration of the application of tranexamic acid and (e) appropriate coagulation testing. We present an algorithm for anticoagulant-associated bleeding and urgent surgery, derived from available data and recommendations, and implemented at our institution. Decisions regarding reversal agents or postponing surgery are based on two questions: the occurrence of a life-threatening bleed or urgent indication for surgery, and the presence of a relevant drug level. Immediate application of reversal agents is suggested if the clinical situation is urgent and laboratory test results are delayed or unavailable. A relevant anticoagulant drug level is required in all other cases. We discuss appropriate laboratory assays for all commonly available anticoagulants, report respective target ranges or expected values, discuss time intervals before surgery, and present critical cut-off values to be used as decision criteria. Specific and unspecific reversal agents for all anticoagulants including the direct oral anticoagulants will be presented. We aim to provide practical guidance for physicians in emergency situations. In addition, we summarise and discuss available experimental and clinical data as well as recommendations provided by scientific societies, authorities and manufacturers.

GD05: Careful Anticoagulation Review in Emergency Medicine (CARe-EM)

Background: The number of patients prescribed anticoagulation for stroke prevention is increasing, along with the proportion of emergency department (ED) patients who are anticoagulant users. Bleeding is the most common side effect. Inappropriate dosing, co-prescription of anti-inflammatories or aspirin, and renal impairment all increase the bleeding risk. An ED visit is an opportunity to review anticoagulant bleeding risks and intervene to prevent bleeding in patients at high risk. Objectives: To establish the 12-month incidence of bleeding in anticoagulated patients visiting the ED, to develop an ED specific anticoagulant-associated bleeding prediction score, to evaluate the ED utility of existing prediction scores. Methods: Research ethics board approval has been granted. Patients will be identified in Hamilton General and Juravinski EDs. Each patient will be followed forward in time for 12 months to document bleeding events. Population: Inclusion criteria: ED patients prescribed warfarin, rivaroxaban, dabigatran, apixaban, edoxaban or low molecular weight heparin (prevalent users). Exclusion criteria: Patients under 16 years of age. Primary outcome: The incidence of major bleeding (defined by ISTH criteria) within 12 months from the index ED visit. Secondary outcomes: Derivation of an ED prediction score to identify patients at high risk of anticoagulant-associated bleeding within 12 months. Tertiary outcomes: Evaluation of ATRIA, modified HAS-BLED and HEMORR2HAGES scores utility in predicting bleeding within 12 months. Data management: The data will be stored anonymously and securely on RedCAP. A literature search/expert discussion has identified multiple potential risk factors for bleeding. This data is collected at the time of the index ED presentation. A committee of emergency, thrombosis, gastroenterology and cardiology physicians will review each major bleeding case. Analysis: Primary analysis: a multiple logistic regression analysis to identify variables associated with major bleeding diagnosed within 12 months of the index presentation. Using the model β coefficients we will derive a simple clinical decision rule. Secondary analysis: assessing the area under the curve and optimal cut points for pre-existing bleeding prediction scores for predicting major bleeding within 12 months. Sample size calculation: With 3000 patients we expect 2700 to be anticoagulated long term, and at least 135/2700 patients will have a major bleed. This is a sufficient number for multivariate analysis to establish a simple model. We estimate 20,000 anticoagulated ED patient attendances/year. Importance: This is the first study to consider the ED visit an opportunity to prevent bleeding. We will establish a method to identify ED patients at high risk of anticoagulant-associated bleeding.

A rapid pro-hemostatic approach to overcome direct oral anticoagulants.

Direct inhibitors of coagulation factor Xa (FXa) or thrombin are promising oral anticoagulants that are becoming widely adopted. The ability to reverse their anticoagulant effects is important when serious bleeding occurs or urgent medical procedures are needed. Here, using experimental mouse models of hemostasis, we show that a variant coagulation factor, FXa(I16L), rapidly restores hemostasis in the presence of the anticoagulant effects of these inhibitors. The ability of FXa(I16L) to reverse the anticoagulant effects of FXa inhibitor depends, at least in part, on the ability of the active site inhibitor to hinder antithrombin-dependent FXa inactivation, paradoxically allowing uninhibited FXa to persist in plasma. Because of its inherent catalytic activity, FXa(I16L) is more potent (by >50-fold) in the hemostasis models tested than a noncatalytic antidote that is currently in clinical development. FXa(I16L) also reduces the anticoagulant-associated bleeding in vivo that is induced by the thrombin inhibitor dabigatran. FXa(I16L) may be able to fill an important unmet clinical need for a rapid, pro-hemostatic agent to reverse the effects of several new anticoagulants.

Novel anticoagulants and antiplatelet agents; a guide for the urologist.

Novel oral anti-coagulants (NOACs) are increasingly being used in clinical practice and are set to almost entirely replace the vitamin K antagonists, such as warfarin, in the near future. Similarly, new antiplatelet agents are now regularly used in place of older agents, such as aspirin and clopidogrel. In an ageing population, with an increasing burden of complex comorbidities, urologists will frequently encounter patients who will be using such agents. Some background knowledge, and an understanding, of these drugs and the issues that surround their usage, is essential. The present article will provide readers with an understanding of these new drugs, including their mechanisms of action, the up-to-date evidence justifying their recent introduction into clinical practice and the appropriate interval for stopping them before surgery. It will also consider the risks of perioperative bleeding for patients taking these drugs and the risks of venous thromboembolism in those in whom they are stopped. Strategies to manage anticoagulant-associated bleeding are discussed.