Safety and Efficacy of Direct Oral Anticoagulants in Patients With Moderate to Severe Cirrhosis.

BACKGROUND: Direct oral anticoagulants (DOACs) remain mostly investigational in patients with moderate to severe hepatic cirrhosis, yet are often selected over traditional anticoagulants including warfarin and enoxaparin in this setting. OBJECTIVE: To determine the safety and efficacy of DOACs in patients with moderate to severe hepatic cirrhosis as compared with traditional anticoagulation. METHODS: This was a retrospective, single-center cohort study evaluating inpatients and outpatients who were prescribed a DOAC, warfarin, or enoxaparin for therapeutic anticoagulation with Child-Turcotte-Pugh (CTP) B or C status at the time that the prescription was written. Included patients were followed until first bleeding or thromboembolic event, or until discontinuation of anticoagulation therapy. Data were collected by manual chart review. The primary outcomes included both bleeding events and thromboembolic events in the DOAC population as compared with traditional anticoagulation. RESULTS: A total of 101 patients were included in the study, 69 treated with DOAC therapy and 32 with traditional anticoagulation. Bleeding events occurred in 36% of patients in the DOAC group and 22% of patients in the traditional group (P = 0.149). In both groups, bleeds were most commonly gastrointestinal. Thromboembolic events occurred in 4% of the DOAC population and no patients in the traditional population (P = 0.55). No fatal bleeding or thromboembolic events occurred. CONCLUSION AND RELEVANCE: DOACs do not appear to be more harmful than traditional anticoagulation in patients with CTP B or C status. These results support the use of DOACs in patients with CTP B or C hepatic cirrhosis when considering safety, efficacy, and convenience.

Evaluation of the Clinical Impact of Thromboprophylaxis in Patients With COVID-19 Following Hospital Discharge.

BACKGROUND: Data are limited regarding the incidence of thromboembolism post-hospital discharge among COVID-19 patients. Guidelines addressing the role of extended thromboprophylaxis for COVID-19 patients are limited and conflicting. OBJECTIVE: The purpose of this study was to evaluate the incidence of post-discharge thromboembolic and bleeding events and the role of thromboprophylaxis among COVID-19 patients. METHODS: A retrospective analysis was conducted of hospitalized patients with symptomatic COVID-19 infection who were discharged from a University of Colorado Health (UCHealth) hospital between March 1, 2020, and October 31, 2020. The primary outcome was objectively confirmed thromboembolism within 35 days post-discharge. The main secondary outcome was the incidence of bleeding events within 35 days post-discharge. Outcomes were compared between those who received extended prophylaxis and those who did not. RESULTS: A total of 1171 patients met the study criteria. A total of 13 (1.1%) of patients had a documented thromboembolic event and 10 (0.9%) patients had a documented bleeding event within 35 days post-discharge. None of the 132 patients who received extended prophylaxis had a thromboembolic event compared to 13 of 1039 who did not receive extended prophylaxis (0 and 1.3%, respectively; P = .383). The incidence of bleeding was higher among patients who received extended prophylaxis compared to those who did not (3.0% vs 0.6%, P = .019). CONCLUSIONS AND RELEVANCE: These results suggest that post-discharge extended prophylaxis may be beneficial for select COVID-19 patients, while carefully weighing the risk of bleeding. Application of our findings may assist institutions in development of thromboprophylaxis protocols for discharged COVID-19 patients.

Eptacog Beta for Bleeding Treatment and Prevention in Congenital Hemophilia A and B With Inhibitors: A Review of Clinical Data and Implications for Clinical Practice.

OBJECTIVE: To review the pharmacology, dosing and administration, safety, clinical efficacy, and role of eptacog beta in the treatment of congenital hemophilia with inhibitors. DATA SOURCES: A literature search of PubMed (1966 to August 2021) was conducted using the keywords eptacog beta, recombinant FVII, and hemophilia. STUDY SELECTION AND DATA EXTRACTION: All relevant published articles and prescribing information on eptacog beta for the treatment of congenital hemophilia with inhibitors were reviewed. DATA SYNTHESIS: Eptacog beta is a novel recombinant activated factor VII (rVIIa) product that demonstrated efficacy in controlling bleeding and associated pain in patients with hemophilia A or B with inhibitors. Eptacog beta has limited Food and Drug Administration-approved and off-label indications compared with other bypassing agents (BPAs; activated prothrombin complex concentrates [aPCC; eptacog alfa]). Eptacog beta costs less than eptacog alfa, but still more than aPCCs. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review provides insight into the role of eptacog beta for treatment of congenital hemophilia with inhibitors and reviews important health system formulary considerations for available BPAs. CONCLUSIONS: Eptacog beta is more cost-effective than eptacog alfa and, as such, may become the preferred rVIIa formulary product. However, eptacog alfa availability remains necessary for the treatment of disorders where eptacog beta has limited data. aPCC should remain the first-line BPA for the treatment of bleeding in patients with inhibitors with no contraindications to use because of its equivocal efficacy and safety and in light of the magnitude of cost savings associated with this strategy.

Direct oral anticoagulants versus warfarin in patients with single or double antibody-positive antiphospholipid syndrome.

Warfarin is recognized as the standard treatment for thrombotic antiphospholipid syndrome (APS); however, direct oral anticoagulants (DOACs) represent appealing therapeutic alternatives given their lack of monitoring and limited drug interactions. A few randomized controlled trials comparing rivaroxaban with warfarin showed an increased risk of recurrent thromboembolism, specifically arterial thrombosis, in patients with high risk forms of APS such as those that are triple antibody positive. We conducted a single-center, retrospective cohort study of all patients within our health system from 2015 to 2020 with a diagnosis of APS (single or double antibody positive) and history of venous thromboembolism. We sought to compare the proportion of patients with a recurrent thrombosis when prescribed a DOAC versus warfarin. Among 96 patients included, 57 were prescribed warfarin and 39 were prescribed a DOAC (90% rivaroxaban). The proportion of patients with a recurrent thromboembolism was almost three times higher in the DOAC group (15.4%) compared to the warfarin group (5.3%), although this was not statistically significant (p = 0.15). Major bleeding was not different between groups. Our findings suggest that rivaroxaban may pose an increased risk for recurrent thromboembolism in low risk APS patients that are single or double-antibody positive compared to warfarin. Results of our study should be cautiously applied to DOACs besides rivaroxaban given their small representation in this study.

Vonicog alfa for the management of von Willebrand disease: a comprehensive review and single-center experience.

Von Willebrand Disease (VWD) is characterized by a qualitative or quantitative defect in von Willebrand factor that results in prolonged bleeding due to the inability to form a stable platelet plug. VWD is the most common inherited bleeding disorder. The mainstay of treatment of VWD includes desmopressin; with plasma-derived von Willebrand Factor concentrates reserved for patients with severe VWD or those with desmopressin intolerability. Although efficacious, plasma-derived factor concentrates can have risks associated with them including minimal risk of pathogenic transmission, potential to contain extraneous plasma proteins and cause severe allergic reactions, and a supply limited by plasma donor availability. Vonicog alfa is a recombinant von Willebrand Factor product. Two phase III trials evaluated the safety and efficacy of vonicog alfa in preventing perioperative bleeding and treating acute bleeding in patients with VWD. Beyond the clinical trials, there has been little real-world experience published regarding experiences with this medication. This article comprehensively reviews the efficacy, safety, pharmacokinetics, and pharmacodynamics of vonicog alfa. These points will be discussed using institutional experiential data from the University of Virginia (UVA) Health System in relation to the clinical studies. The goal of this review article is to offer insights to clinical directions, discuss operational challenges, and offer guidance for future studies and formulary decisions.

Antithrombin supplementation in adult patients receiving extracorporeal membrane oxygenation.

INTRODUCTION: Extracorporeal membrane oxygenation is associated with an increased risk of thrombosis and hemorrhage. Acquired antithrombin deficiency often occurs in patients receiving extracorporeal membrane oxygenation, necessitating supplementation to restore adequate anticoagulation. Criteria for antithrombin supplementation in adult extracorporeal membrane oxygenation patients are not well defined. METHODS: In this retrospective observational study, adult patients receiving antithrombin supplementation while supported on extracorporeal membrane oxygenation were evaluated. Antithrombin was supplemented when anti-Xa levels were subtherapeutic with unfractionated heparin infusion rates of 15-20 units/kg/h and measured antithrombin activity <50%. Patients were evaluated for changes in degree of anticoagulation and signs of bleeding 24 hours pre- and post-antithrombin supplementation. RESULTS: A total of 14 patients received antithrombin supplementation while on extracorporeal membrane oxygenation. The median percentage of time therapeutic anti-Xa levels were maintained was 0% (0-43%) and 40% (9-84%) in the pre-antithrombin and post-antithrombin groups, respectively (p = 0.13). No difference was observed in the number of patients attaining a single therapeutic anti-Xa level (pre-antithrombin = 6, post-antithrombin = 13; p = 0.37) or unfractionated heparin infusion rate (pre-antithrombin = 7.35 (1.95-10.71) units/kg/h, post-antithrombin = 6.81 (3.45-12.58) units/kg/h; p = 0.33). Thirteen patients (92%) achieved an antithrombin activity at goal following supplementation. Antithrombin activity was maintained within goal range 52% of the time during the replacement period. Four bleeding events occurred pre-antithrombin and 10 events post-antithrombin administration (p = 0.26) with significantly more platelets administered post-antithrombin (pre-antithrombin = 0.5 units, post-antithrombin = 4.5 units; p = 0.01). CONCLUSION: Therapeutic anticoagulation occurred more frequently following antithrombin supplementation; however, this difference was not statistically significant. More bleeding events occurred following antithrombin supplementation while observing an increase in platelet transfusions.

Direct oral anticoagulants in hypercoagulable states.

Direct oral anticoagulants have been shown safe and effective in the treatment of pulmonary emboli and deep vein thrombi. Their role in the treatment of patients with hypercoagulability is uncertain. We designed a retrospective exploratory analysis of all patients with definite heparin induced thrombocytopenia (HIT) and antiphospholipid syndrome (APS) that were treated with either apixaban or rivaroxaban from September 2011 through November 2015. Patients were reviewed for several clinico-pathologic features, including efficacy and safety. 23 patients were identified (12 patients with HIT and 11 patients with APS). Sixteen patients (70 %) were treated with apixaban and seven patients (30 %) were treated with rivaroxaban over a median follow up of 7 months (range 2-39). Zero patients developed recurrent thrombi. Two patients being treated for HIT developed major bleeding leading to discontinuation of all anticoagulation. Therefore, apixaban and rivaroxaban appear safe and effective for treatment of patients with HIT and APS in this small retrospective cohort and should be considered on an individual basis for patients who refuse, fail or are intolerant of warfarin. There were no sources of funding.

A Novel Laboratory Assay to Monitor Unfractionated Heparin Dosing in Patients Taking Apixaban Prior to Hospital Admission.

INTRODUCTION: When monitoring heparin, anti-Xa assays are susceptible to interference from apixaban taken before admission and can result in inappropriate dose adjustments that can negatively affect patient care. METHODS: We derived a novel assay, termed corrected heparin (CH), using quantified values from a chromogenic anti-Xa assay with heparin calibrators before and after heparinase treatment to eliminate any interference from apixaban within the patient sample. We retrospectively assessed 469 specimens from 72 patients at our institution who had their unfractionated heparin infusion monitored using the CH assay because of known apixaban use. These patients were included in the study if they had detectable apixaban levels (>0.1 IU/mL by anti-Xa). RESULTS: The analytical performance of the assay was evaluated, and precision was found to be 8.8% within 1 day and 13.3% over multiple days, with acceptable linearity (R2 = 0.997). Evaluation of clinical performance was compared with the partial thromboplastin time (PTT), showing a lack of correlation similar to comparisons between the PTT and anti-Xa assay (Blood Coagul Fibrinolysis 1993;4:635-8). The mean time to a therapeutic result in this cohort was 10 hours and 10 minutes. The CH assay was used to determine how long the apixaban was detected by the anti-Xa assay. The majority of patients (80%) still had measurable anti-Xa assay interference from apixaban at 24 hours after the last apixaban dose. CONCLUSIONS: We have developed and evaluated an assay capable of quantifying heparin in the presence of apixaban. This assay showed acceptable performance in both analytical and clinical performance.

The Relationship between the Initial Anti-factor Xa Measurement and the Duration of Direct Oral Anticoagulant Influence in Patients Transitioning to Heparin.

BACKGROUND: Anticoagulation monitoring during transition from direct oral anticoagulants (DOAC) to heparin infusions is a significant challenge. Factor Xa inhibitors influence the heparin calibrated antifactor Xa assay. The University of Virginia (UVA) Medical Center utilized a corrected antifactor Xa assay (c-AXA) during this transition period, which removes DOAC-mediated antifactor Xa activity (d-AXA) and reflects heparin-specific activity. Currently, the duration of this influence is not well described. STUDY OBJECTIVE: This study had two aims: to determine if the initial d-AXA is predictive of the duration of DOAC influence and to further characterize this influence among different patient populations. METHODS: This retrospective study included adult patients admitted to UVA Medical Center between September 2016 and March 2017, with c-AXA measurements, who received apixaban or rivaroxaban within 48 hours before heparin initiation. A Pearson correlation test, Kaplan-Meier Survival Analysis, and multivariate linear regression were used to assess the relationship between initial d-AXA and duration of influence. RESULTS: Sixty-eight patients met inclusion criteria and were maintained on either apixaban (85%) or rivaroxaban (15%) before heparin initiation. The initial d-AXA ranged from 0.11 to 3.27 IU/ml. The mean duration of influence was 69.3 ± 46.2 hours, with a median duration of 62.7 hours. No strong correlation was identified between initial d-AXA and duration of influence (R2 = 0.124). Presence of interacting medications significantly increased duration of influence (p=0.012). No significant difference in duration of influence existed between patients with normal renal function and those with dynamic renal function (p=0.84), or with body mass index (BMI) greater than 40 kg/m2 (p=0.16). CONCLUSIONS: The initial d-AXA was not predictive of duration of influence in patients transitioning from DOACs to heparin infusion; however, the median duration of influence suggests influence may be present for longer than currently stated in the literature, especially in those taking interacting medications.

Heparin-Induced Thrombocytopenia and Cardiac Surgery.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated condition characterized by thrombocytopenia with possible arterial and/or venous thrombosis. The overall incidence of HIT is low but ranges from 0.1% to 5%.1,2 The incidence can be as high as 3% in patients undergoing cardiac surgery. The use of unfractionated heparin (UFH) is ubiquitous in patients who undergo cardiac procedures and carries a 10-fold higher incidence of HIT over low molecular weight heparin. Patients undergoing cardiac surgery thus form a unique group that warrants specific attention to this clinicopathologic entity considering the relatively high incidence and associated morbidity and mortality with a delay in diagnosis. In this article, we will discuss 5 clinical aspects pertinent to the diagnosis and management of HIT in cardiac surgery patients and review the current literature.

The sample that would not clot.

BACKGROUND: Vitamin K is a vital component within both the intrinsic and extrinsic coagulation cascade as certain factors (II, VII, IX, X and protein C and S) utilize vitamin K as a cofactor during post translational modification. Deficiency of vitamin K can result in the inability to properly form blood clots, both in vivo and in vitro, due to reduced vitamin K dependent factor levels and function. Vitamin K deficiency can result from congenital causes, such as VKOR or CYP2C9 mutations, or acquired causes, such as nutritional deficiencies, antibiotic therapy, or supra-therapeutic warfarin dosing. RESULTS: In this case we present a patient with multifactorial vitamin K deficiency (due to nutritional defects and multiple genetic mutations in VKOR and CYP2C9) that was exacerbated by antibiotic and warfarin therapy during her hospital admission. CONCLUSION: This case displays the importance of genetic testing prior to warfarin dosing and the role antibiotics play in the coagulation cascade.

Safety and effectiveness of apixaban compared to warfarin in dialysis patients.

Background: The use of apixaban for stroke prophylaxis or for the treatment of venous thromboembolism in end stage renal disease (ESRD) patients maintained on dialysis is based on one single-dose pharmacokinetic study. There is a deficiency of clinical evidence supporting safety in this population.Objective: The purpose of this study was to determine the safety and efficacy of apixaban compared with warfarin in dialysis patients.Patients/methods: This is a retrospective cohort study conducted at the University of Virginia Medical Center. A total of 124 ESRD patients maintained on dialysis who either received apixaban (n = 74) or warfarin (n = 50) between January 1, 2014 and October 31, 2016 were included in the study. We used multivariable logistic regression to compare the likelihood of patients experiencing a bleeding event based on anticoagulant therapy.Results: The apixaban group experienced fewer overall bleeding events than the warfarin group (18.9% vs 42.0%; P = .01); this significant difference persisted in adjusted analysis (OR = 0.15; 95% CI = 0.05-0.46; P = .001). Major bleeding events were less frequent in the apixaban group compared with patients on warfarin (5.4% vs 22.0%; P = .01). There were no recurrent ischemic strokes in either groups. A lower, non-significant, incidence of recurrent VTE was found in patients on apixaban compared with warfarin (4.4% vs 28.6%; P = .99).Conclusion: Compared to warfarin, our findings suggest that apixaban is a safe and effective alternative in patients with ESRD maintained on dialysis, with apixaban patients experiencing fewer bleeding events than warfarin patients.

Risk of Major Bleeding with Ibrutinib.

BACKGROUND: The Bruton tyrosine kinase inhibitor, ibrutinib, is an effective therapy against mature B-cell malignancies. Although generally well tolerated, serious bleeding emerged during developmental clinical trials as an unexpected, although uncommon, adverse event. As the use of ibrutinib increases outside of the clinical trial setting and in patients with more comorbidities, the rate of major bleeding could be greater. MATERIALS AND METHODS: A retrospective analysis the data from all patients at our center and its regional clinics who had been prescribed ibrutinib from January 2012 to May 2016 were reviewed for demographic data, comorbid illnesses, bleeding events, and concurrent medications. RESULTS: We identified 70 patients. Bleeding of any grade occurred in 56% of patients, mostly grade 1 to 2 bruising and epistaxis. Major bleeding, defined as grade ≥ 3, occurred in 19% of patients, greater than previously reported. Anemia (hemoglobin < 12 g/dL; hazard ratio [HR], 5.0; 95% confidence interval [CI], 1.4-18.2; P = .02) and an elevated international normalized ratio (> 1.5; HR, 9.5; 95% CI, 2.7-33.5; P < .01) at ibrutinib initiation were associated with an increased risk of major bleeding. Of those with major bleeding, most patients were also taking an antiplatelet agent (70%), an anticoagulant (17%), or a CYP 3A4 inhibitor (7%), with 13% taking both antiplatelet and anticoagulant medications. The use of both antiplatelet and anticoagulant therapy significantly increased the risk of a major bleed event (HR, 19.2; 95% CI, 2.3-166.7; P < .01). CONCLUSION: The results of the present study have demonstrated a greater rate of major bleeding with ibrutinib use in a standard clinical setting than previously reported. Patients with anemia or an elevated international normalized ratio or requiring anticoagulant and/or antiplatelet medications during ibrutinib therapy have a significantly increased risk of major bleeding. Careful consideration of the risks and benefits for this population is needed. The combination of antiplatelet and anticoagulation medications with ibrutinib therapy is of particular concern.