Bleeding-related Adverse Events Research Articles

Variceal bleeding following treatment with atezolizumab plus bevacizumab in two patients with unresectable hepatocellular carcinoma.

Bleeding-related adverse events may occur due to anti-vascular endothelial growth factors. Here, we report two cases of variceal rupture during atezolizumab plus bevacizumab (ATZ/BV) treatment for unresectable hepatocellular carcinoma (u-HCC).Case 1 involved a man in his 60s with alcoholic liver cirrhosis (LC) and u-HCC. Seventy-four days after ATZ/BV administration, the patient was admitted for hematemesis. Upper esophagogastroduodenoscopy (EGD) revealed worsening of the esophageal varices (EVs) to F2 grade with active bleeding. Endoscopic variceal ligation successfully achieved hemostasis.Case 2 involved a man in his 70s with alcoholic LC and u-HCC. The patient was admitted with hematemesis 114days after ATZ/BV administration. During EGD, the EVs deteriorated to F3 grade, although hemostasis had already been achieved. The evaluation was discontinued during the observation stage because of the worsening hepatic reserve.Neither patient had EVs warranting prophylactic treatment before ATZ/BV administration, showed a partial tumor response, or had portal vein tumor thrombus. Both patients demonstrated increased total diameters of the collateral veins and splenic volume compared to those before treatment. These findings suggest that ATZ/BV treatment may increase portal pressure. In conclusion, the administration of ATZ/BV to patients with LC and u-HCC necessitates careful management of EVs aggravation and rupture.

Pharmacokinetics, pharmacodynamics, and safety of asundexian in healthy Chinese and Japanese volunteers, and comparison with Caucasian data.

There is an unmet clinical need for effective anticoagulant therapies for the management of thromboembolic diseases that are not associated with a relevant risk of bleeding. Asundexian (BAY 2433334) is an oral, direct, small-molecule inhibitor of activated factor XI (FXIa). Phase I data from healthy Caucasian male participants indicated predictable pharmacokinetic (PK) and pharmacodynamic (PD) profiles and no clinically relevant bleeding-related adverse events (AEs). Reported here are data from two phase I, randomized, placebo-controlled, single- and multiple-dose escalation studies of asundexian conducted in 60 healthy men: 24 Japanese and 36 Chinese. Baseline characteristics were comparable between the treatment groups. All treatment-emergent AEs were mild, with no serious AEs or AEs of special interest reported. Systemic exposure to asundexian increased dose proportionally after single or multiple dosing, with relatively low accumulation following multiple once-daily dosing in both Chinese and Japanese volunteers. Asundexian induced dose-dependent prolongation of activated partial thromboplastin time and inhibition of FXIa activity, with no effects on prothrombin time or FXI concentration in Japanese participants. There were no clinically relevant interethnic differences in PK profile across the Japanese, Chinese, and Caucasian (data from the previous phase I study) participants and no clinically relevant difference in PD response between Japanese and Caucasian participants.

Unraveling Postoperative Bleeding Dynamics in Laparoscopic Roux-en-Y Gastric Bypass: Insights from a Single-Center Tranexamic Acid Study.

The efficacy of postoperative tranexamic acid (TXA) administration in mitigating bleeding after primary laparoscopic Roux-en-Y gastric bypass (RYGB), a prevalent complication associated with significant morbidities and mortality, and the use of sequential laboratory parameter changes in bleeding screening and TXA impact tracking were investigated. This retrospective analysis included RYGB patients (aged 18-65years, with a body mass index of 35-50kg/m2) over 5years who were categorized into three groups by evolving treatment regimens: Group A (n = 42) received standard pre- and postoperative enoxaparin (30mg) every 12h; Group B (n = 160) received enoxaparin and postoperative TXA (250mg every 6h); and Group C (n = 73) received TXA alone. Postoperative bleeding-related adverse events, vital signs, and laboratory changes were compared. Postoperative hemorrhage occurred in 3.6% (10/275) of patients, with no significant intergroup differences. Patients who experienced bleeding had greater decreases in hemoglobin (∆Hb) (2.1 vs. 1.4; p = 0.003), greater ∆Hb > 2 (50% vs. 15%; p = 0.013), and greater use of staples than did those who did not experience bleeding (8 vs. 7; p = 0.001). The ∆Hb values were lower in Groups B (1.4) and C (1.3) than in Group A (1.7, p = 0.011). No significant difference was noted between Groups C and B. This study emphasizes the potential of TXA to mitigate postoperative bleeding after RYGB, with no added benefit from excluding enoxaparin. Monitoring patients with a ∆Hb > 2mg/dl and increased stapler usage is crucial. Further research is needed to validate routine TXA use across different procedures.

Minimally modified human blood coagulation factor X to bypass direct factor Xa inhibitors

BackgroundDirect oral factor (F)Xa inhibitors are widely used as alternatives to conventional vitamin K antagonists in managing venous thromboembolism and nonvalvular atrial fibrillation. Unfortunately, bleeding-related adverse events remain a major concern in clinical practice. In case of bleeding or emergency surgery, rapid-onset reversal agents may be required to counteract the anticoagulant activity. ObjectivesThe ability of FXa variants to bypass the direct oral FXa inhibitors was assessed. MethodsHuman FXa variants were generated through substitution of phenylalanine 174 (F174) for either alanine, isoleucine, or serine. FXa variants were stably expressed in HEK293 cells and purified to homogeneity using ion-exchange chromatography. ResultsF174-substituted human FX variants demonstrated efficacy in restoring thrombin generation in plasma containing direct FXa inhibitors (apixaban, rivaroxaban, edoxaban). Their ability to bypass the anticoagulant effects stems from a significantly reduced sensitivity for the direct FXa inhibitors due to a decrease in binding affinity determined using molecular dynamics simulations and free energy computation. Furthermore, F174 modification resulted in a partial loss of inhibition by tissue factor pathway inhibitor, enhancing the procoagulant effect of F174-substituted FX. Consequently, the F174A- and F174S-substituted FX variants effectively counteracted the effects of 2 widely used anticoagulants, apixaban and rivaroxaban, in plasma of atrial fibrillation and venous thromboembolism patients. ConclusionThese human FX variants have the potential to serve as a rescue reversal strategy to overcome the effect of direct FXa inhibitors in case of life-threatening bleeding events or emergency surgical interventions.

Clinical and molecular determinants of bleeding-related adverse outcomes in high-grade glioma.

Cancer is an independent risk factor for the development of venous thromboembolism (VTE). However, patients with high-grade glioma (HGG) including glioblastoma (GBM) are at a particularly high risk of VTE with an incidence up to 20-30% per year. Patients are often placed on anticoagulation if they are found to have VTE. However, patients with primary brain tumors such as HGG are at increased risk for intracerebral hemorrhage (ICH) even without the administration of anticoagulation. The combination of risk factors for ICH with anticoagulation and HGG complicates decision-making. Currently it is not known which of the direct oral anticoagulants (DOACs) are safest for patients with HGG in terms of adverse bleeding-related outcomes such as ICH. Furthermore, a deeper understanding of the clinical and molecular determinants of bleeding-related adverse outcomes in HGG is not fully characterized. In this retrospective study, we identified and gathered data on 75 consecutive patients with pathology-confirmed HGG with hospital encounters at two academic medical center hospitals in Austin between July 1, 2017 and June 30, 2022. We compared clinical and treatment-related factors among cohorts who had received various forms of anticoagulation or no anticoagulation. Patients who were on rivaroxaban (3/7 (43%)) had a statistically significant association with more bleeding-related adverse events compared to those on apixaban (0/12 (0%)) or enoxaparin (0/5 (0%), p = 0.022) even though the groups were similar in characteristics including total time on the respective anticoagulation. Patients on anticoagulation vs those never on anticoagulation did not differ in terms of their studied demographic and clinical characteristics. Intriguingly, logistic regression analysis revealed that patients Astrocytoma, isocitrate dehydrogenase (IDH) mutant, grade 4 had a significant association with more adverse bleeding-related events even when controlling for other relevant factors (Odds Ratio compared to reference GBM: 49.4, 95% CI: 2.8, 2084.7; p = 0.013). In this study we found that the use of rivaroxaban was associated with more bleeding-related events compared to apixaban and enoxaparin in patients with high-grade glioma. In this study we also found that the diagnosis of astrocytoma, IDH mutant, grade 4 was associated with more bleeding events. However, this is based on a small study and there is a need for larger studies to further evaluate these results.

EPID-08. CLINICAL AND MOLECULAR DETERMINANTS OF BLEEDING-RELATED ADVERSE OUTCOMES IN HIGH-GRADE GLIOMA

Abstract Cancer is an independent risk factor for the development of venous thromboembolism (VTE) however patients with high-grade glioma (HGG) including glioblastoma (GBM) are at a particularly high risk of VTE with an incidence up to 20- 30% per year. Patients are often placed on anticoagulation to reduce the risk of VTE. However, patients with primary brain tumors such as HGG are at increased risk for intracerebral hemorrhage (ICH) even without the administration of anticoagulation. The combination of risk factors for ICH with anticoagulation and HGG complicates decision-making. Currently it is not known which of the direct oral anticoagulants (DOACs) are safest for patients with HGG in terms of adverse bleeding-related outcomes such as ICH. Furthermore, a deeper understanding of the clinical and molecular determinants of bleeding-related adverse outcomes in HGG is not fully characterized. In this study, we gathered data on patients with HGG from two Ascension Seton Hospitals in the Austin metro area from July 1, 2017 through June 30, 2022. We identified 76 pathology-confirmed patients with HGG. Patients who were on rivaroxaban (3/7 (43%), p=.022) had a statistically significant association with more bleeding-related adverse events compared to those on apixaban (0/12 (0%)) or enoxaparin (0/5 (0%)) even though the groups were similar in terms of their characteristics including total time on the respective anticoagulation. Patients on anticoagulation vs those never on anticoagulation did not differ in terms of their studied demographic and clinical characteristics. Intriguingly, logistic regression analysis revealed that patients harboring isocitrate dehydrogenase (IDH) mutations had a statistically significant association with more adverse bleeding-related events even when controlling for other relevant factors (Odds Ratio compared to reference GBM: 115.7; p=.014). This study offers insights into our understanding of relevant factors associated with worse bleeding-related adverse outcomes such as ICH in patients with HGG.

Decreased Bleeding-Related Adverse Events Using Track Embolization with Gelatin Sponge Slurry after Percutaneous Liver Biopsy: A Propensity Score–Matched Study

PurposeTo evaluate the effectiveness of track embolization using gelatin sponge slurry in percutaneous ultrasound (US)-guided liver biopsy. Materials and MethodsAmong the 543 patients who underwent percutaneous US-guided liver biopsies between September 2018 and August 2021, 338 who did not undergo track embolization and 105 who underwent track embolization were included in the analysis. All procedures were performed with 18-gauge coaxial core biopsy needles. Patients’ laboratory data were reviewed. Patients in both groups were subdivided into the following 2 groups: (a) those with targeted biopsy for a focal liver lesion and (b) those with nontargeted biopsy for a liver parenchyma. Moreover, postbiopsy events, such as transfusion and transarterial embolization, were assessed. To minimize selection bias, propensity score matching (PSM) was performed. ResultsAfter PSM, all factors that could affect bleeding risk were well-matched and well-balanced between the 2 groups (P > .474). In the non-track embolization group, 17 (16.2%) patients experienced major or minor bleeding-related adverse events (AEs). In contrast, in the track embolization group, only 5 (4.8%) patients experienced major or minor bleeding-related AEs, which was significantly lower than that in the non-track embolization group (P = .007). All 5 (4.8%) cases of major bleeding-related AEs were observed in the non-track embolization group (P = .024). ConclusionsIn this study, a retrospective analysis was performed using PSM for percutaneous US-guided liver biopsy. Track embolization using gelatin sponge slurry is significantly superior in the prevention of bleeding-related AEs after US-guided liver biopsy.

Pooled analysis of two phase 3 trials evaluating the effects of a novel combined oral contraceptive containing estetrol/drospirenone on bleeding patterns in healthy women

ObjectiveTo evaluate the bleeding patterns of a new combined oral contraceptive containing estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg in a 24/4-day regimen. Study designWe pooled bleeding data from two parallel, open-label, 13-cycle phase 3 trials that enrolled participants 16 to 50 years old with body mass index (BMI) ≤35 kg/m2. Participants reported vaginal bleeding/spotting in daily diaries. For this bleeding analysis, we included participants with at least one evaluable cycle. We calculated mean frequencies of scheduled and unscheduled bleeding/spotting episodes and median duration of bleeding/spotting episodes, and assessed associations between treatment compliance, BMI and recent hormonal contraceptive use on bleeding/spotting outcomes. ResultsWe included 3409 participants with 33,815 cycles. Scheduled bleeding/spotting occurred in 87.2% to 90.4% of participants/cycle, with a median duration of 4 to 5 days. Unscheduled bleeding/spotting decreased from 27.1% in Cycle 1 to 20.6% in Cycle 2 to ≤17.5% from Cycle 5 onwards. Most (66.5%) unscheduled bleeding/spotting episodes were spotting-only. Between 5.8% and 7.8% of users/cycle experienced absence of any scheduled or unscheduled bleeding/spotting. Missing one or more active pills resulted in a higher occurrence of unscheduled bleeding/spotting (adjusted odds ratio [aOR] 2.13 [95% confidence interval 1.68–2.70]) and absence of scheduled bleeding/spotting (aOR 2.36 [1.82−3.07]). Participants with a BMI ≥30 kg/m2 reported more absence of scheduled bleeding/spotting (aOR 1.68 [1.37−2.05]). Switchers and starters reported similar frequencies of unscheduled bleeding/spotting (aOR 0.94 [0.83−1.07]) and absence of scheduled bleeding/spotting (aOR 1.00 [0.85−1.19]). Three percent of participants discontinued for a bleeding-related adverse event. ConclusionE4/DRSP use results in a predictable bleeding pattern with limited unscheduled bleeding/spotting. Noncompliance and BMI affect bleeding patterns. Implications statementMost estetrol/drospirenone users experience a predictable and regular bleeding pattern. Providers can educate patients about the expected bleeding patterns and should advise users that they may infrequently experience no scheduled bleeding/spotting. This information may improve user acceptability and continuation of this new oral contraceptive.

EGb 761® Does Not Affect Blood Coagulation and Bleeding Time in Patients with Probable Alzheimer's Dementia-Secondary Analysis of a Randomized, Double-Blind Placebo-Controlled Trial.

Following reports of bleeding upon Ginkgo intake, we assessed whether Ginkgo extract EGb 761® affects coagulation or platelet function or increases the risk of bleeding. In a double-blind, placebo-controlled trial, prothrombin time, activated partial thromboplastin time, international normalized ratio and bleeding time were measured in patients with Alzheimer’s dementia at baseline, weeks 6 and 26. A total of 513 patients were randomized to 120 mg (n = 169) or 240 mg EGb 761® (n = 170) or placebo (n = 174). No relevant changes were found for coagulation parameters and bleeding time. Numbers of bleeding-related adverse events were similar in all groups. Concomitant intake of acetylsalicylic acid was documented for 68 patients in the placebo group and 105 in the EGb 761® groups. Within these groups, the means at baseline and week 26 differed by less than 1 unit for prothrombin time and bleeding time and less than 0.1 unit for international normalized ratio. Data on warfarin treatment in nine patients each taking placebo or EGb 761® did not indicate enhancement of warfarin effects by EGb 761®. No evidence was found that EGb 761® affects hemostasis or increases the bleeding risk. No pharmacodynamic interactions with warfarin or acetylsalicylic acid were found.

Cost-Consequence Model Comparing Eltrombopag and Romiplostim for Pediatric Patients with Previously-Treated Chronic Immune Thrombocytopenia

BACKGROUND: Immune thrombocytopenia (ITP) is an auto-immune disorder characterized by enhanced platelet destruction and, subsequently, increased bleeding risk. It is a chronic condition (cITP) in many patients. In pediatric patients, severe thrombocytopenia may limit activities and those patients who have an insufficient response to therapy may be at risk of severe, potentially life-threatening bleeding complications. Thrombopoietin receptor (TPO-R) agonists have recently emerged as promising therapies for cITP patients who are refractory to other treatments. While eltrombopag (EPAG) is the only TPO-R agonist FDA approved for use in pediatric patients, romiplostin (ROMI) has been used in Phase 3 clinical studies.OBJECTIVES: This study's objective was to develop an economic model to compare the costs and benefits of EPAG with ROMI in pediatric cITP in the US.METHODS: A cost-consequence model was developed using a decision tree approach to evaluate the costs of EPAG and ROMI relative to treatment success in previously-treated pediatric patients. Data on platelet count response rate, bleeding events, and adverse events were derived from all relevant identified phase III registered clinical trials; health outcomes were compared via indirect treatment comparison. Costs incorporated in the model included drugs and administration, routine care, rescue medications, bleeding-related adverse events, other adverse events, and mortality costs.RESULTS: A summary of the cost and efficacy results is presented in Figure 1. The overall estimated cost of EPAG per patient was $66,550, compared to $101,056 for ROMI. EPAG's lower cost compared to ROMI was largely due to lower drug costs ($62,202 vs. $84,396), administration costs ($0 vs. $1,955), and significantly lower costs due to severe bleeding ($354 vs. $10,191). Regarding outcomes, EPAG demonstrated a 22.1% incremental benefit over ROMI when assessing severe bleeding events. Moderate bleeding (WHO grade 2) was also evaluated, where EPAG had a 15.7% incremental benefit over ROMI. EPAG again showed a benefit over ROMI, with an incremental benefit of 2.3% over ROMI when platelet response was assessed.When considering cost per severe bleeding event avoided, EPAG was dominant over ROMI (less expensive and more effective). EPAG was again dominant over ROMI when assessing the cost per responder and per bleeding event (any grade) . Sensitivity analysis was consistent with the base case findings, with results most sensitive to variations in platelet response rate and changes in primary therapy prices.CONCLUSIONS: TPO-R agonists are favourable options for the treatment of pediatric patients with cITP who have had an insufficient response to corticosteroids or immunoglobulins. We showed that EPAG was the preferred TPO-R agonist to treat cITP when indirectly compared to ROMI, largely driven by its favorable severe bleeding outcomes and lower drug and administration costs.Figure 1: Eltrombopag versus Romiplostim, Cost and Efficacy Results [Display omitted] DisclosuresBhor:Novartis: Employment, Equity Ownership, Research Funding. Roy:Novartis: Employment, Equity Ownership. Elliott:Novartis: Employment. Briggs:Novartis: Consultancy.

Incidence of Atrial Fibrillation and Bleeding in CLL Patients Treated with Ibrutinib: Evidence from the Veterans Health Administration

Background: Chronic Lymphocytic Leukemia (CLL) is the second most common type of leukemia in adults, with an estimated 62,130 new cases expected to be diagnosed in 2017 (Siegel, Miller, and Jemal 2017). The introduction of novel oral agents in CLL, starting with ibrutinib (IB) in 2013, has revolutionized the therapeutic landscape, with efficacy and safety that compare favorably overall with prior mainstays of treatment such as chemoimmunotherapy. However, novel agents are associated with specific toxicities that may limit their utility. Several clinical trials have suggested that there is an association between IB and the risk of bleeding-related adverse events and atrial fibrillation (Afib) in CLL patients (Leong et al. 2016; McMullen et al. 2014; Lipsky et al. 2015). The risk of bleeding and Afib in CLL patients treated with IB in a real-world clinical setting is unknown.Aims: This study examines the real-world incidence of bleeding and Afib in CLL patients receiving IBR in the Veterans Health Administration (VHA). We also report the utilization of anticoagulant and antiplatelet medications following treatment with IB. For comparison, the incidence of bleeding and Afib and use of anticoagulant and antiplatelet medications during treatment in a cohort of CLL patients treated with bendamustine and rituximab (BR) is also reported.Methods: Patients who were diagnosed and treated for CLL at the VHA from 2010-2014 were identified through the VA Clinical Cancer Registry (VACCR). Patients were excluded if they had a prior malignancy. Patients were followed until the end of study observation period, death, or lack of utilization of hematology/oncology services for 18 months, or incidence of another cancer. For the IB cohort, patients were indexed at the time of the first dispensation of IB. Comorbidities and medications that could influence incidence of bleeding or Afib were extracted in the six months prior to the index date while the incidence of bleeding and Afib was extracted in the six months following the index date. Charlson Comorbidity Index (CCI),(Deyo 1992; D'Hoore, Bouckaert, and Tilquin 1996) liver disease (cirrhosis, alcoholic liver disease, HCV infection)(Kramer et al., n.d.), and diabetes (controlled and uncontrolled) were examined (Guzman et al. 2014). Treatments dispensed, evidence of VHA system use, bleeding events, and Afib were determined from the administrative records, lab records, pharmacy dispensation records, and clinical notes in the electronic medical record. Descriptive statistics were used to report estimates.Results: From 2010-2014, 2,796 patients were diagnosed and received care for their CLL within the VHA. We identified 172 patients receiving IB and 291 patients receiving BR (table 1).Of the BR patients, 282 (97%) were male. Similarly, 167 (97%) of IB patients were male. The median age at diagnosis was 67 years for BR patients and 69 years for IB patients. The CCI, liver disease and end-stage liver disease comorbidities were higher in patients receiving BR than IB, however, there were significantly more patients with diabetes (both controlled and uncontrolled) who received IB (24%) compared to those who received BR (8%). The use of anticoagulants following induction therapy did not differ between BR and IB patients (9% v 8%), nor did the use of antiplatelets (6% v 2%). Incidence of anticoagulants and antiplatelet usage prior to BR or IB induction therapy was minimal (fewer than 10 patients) and is therefore not reported. Of the 291 patients that received BR, 12 (4%) developed a bleeding event compared to 20 (12%) of the 172 patients that received IB. Additionally, 13 (8%) of IB patients developed Afib compared to only 3% of BR patients.Conclusions: Real-world evidence from a nationwide cohort of CLL patients suggest that while IB is associated with increased bleeding-related adverse events and Afib it is comparable to those reported in previous clinical trials (Leong et al. 2016; Lipsky et al. 2015). Additionally, these findings suggest that patients in real-world clinical care settings with higher levels of comorbidities may be at an increased risk for bleeding events and Afib. [Display omitted] DisclosuresHalwani:Kyowa Hikko Kirin: Research Funding; Bristol Myers Squib: Research Funding; Seattle Genetics: Research Funding; Roche/Genentech Inc.: Research Funding; Genetech Inc.: Research Funding; Takeda: Research Funding; Pharmacyclics: Research Funding; Amgen: Research Funding; AbbVie: Research Funding; Immune Design: Research Funding; Miragen: Research Funding. Sauer:AbbVie: Research Funding; Genentech Inc.: Research Funding; Pharmacyclics: Research Funding; Amgen: Research Funding.

Evaluating medical device adverse event signals using a likelihood ratio test method

ABSTRACT Signal detection methods have been used extensively in post-market surveillance to identify elevated risks of adverse events. However, these statistical methods have not been widely used in detecting AE signals for medical devices. In this paper, we focused on the use of a likelihood ratio test (LRT)-based method in identifying adverse event (AE) signals associated with left ventricular assist devices (LVADs) using Medical Device Reporting (MDR) data. Among 110,927 adverse event entries identified in MDR data for LVADs, the LRT method detected 18 AE signals which included seven bleeding-related AEs such as hemolysis, thrombosis, hematuria, thrombus, blood loss, and hemorrhage. The LRT method was also applied to longitudinal data from 2007 to 2019 where a monotone alpha-spending function was used to ensure the control of type I error at each look and overall for trend analysis. Furthermore, the LRT method was compared to proportional reporting ratios (PRRs), Bayesian confidence propagation neural network (BCPNN), and simplified Bayes methods and found to be the most conservative method when examining the total number of detected signals, given its ability to control type-I error and the false discovery rate.

Caplacizumab: an anti-von Willebrand factor antibody for the treatment of thrombotic thrombocytopenic purpura.

The pharmacology, pharmacokinetics, efficacy, safety, dosing and administration, and place in therapy of caplacizumab, a novel antibody fragment that inhibits von Willebrand factor, for the treatment of acquired thrombotic thrombocytopenic purpura (TTP) are summarized. Caplacizumab is a humanized anti-von Willebrand factor monoclonal antibody fragment that inhibits the interaction between ultralarge von Willebrand factor multimers and platelets. Caplacizumab is indicated for use in combination with standard-of-care modalities such as plasma exchange and immunosuppressive therapy for the treatment of adults with acquired TTP. By inhibiting von Willebrand factor, caplacizumab offers a new approach to the management of TTP by preventing the development of potentially life-threatening microvascular thrombosis that can occur in the disease process. In a randomized, placebo-controlled phase 3 trial, patients with acquired TTP treated with caplacizumab had more rapid platelet level normalization than placebo users; caplacizumab use also resulted in lower rates of disease recurrence and TTP-related death. The most common adverse events associated with caplacizumab use are bleeding-related events. In a phase 3 trial, serious bleeding-related adverse events were reported in 8 patients (11%) in the caplacizumab group and 1 patient (1%) in the placebo group. Caplacizumab is administered as an 11-mg intravenous loading dose 15 minutes prior to plasma exchange, followed by administration of 11 mg subcutaneously daily after plasma exchange. Once-daily caplacizumab administration can be continued for 30 days after the last plasma exchange. The medication and supplies for administration are provided as a single-use kit; patients should be trained on proper reconstitution and self-administration technique prior to the use of caplacizumab in the ambulatory setting. Caplacizumab is a first-in-class von Willebrand factor inhibitor approved for the treatment of adults with acquired TTP.

Safety of OnabotulinumtoxinA with Concomitant Antithrombotic Therapy in Patients with Muscle Spasticity: A Retrospective Pooled Analysis of Randomized Double-Blind Studies.

BackgroundOnabotulinumtoxinA is approved as a treatment across multiple indications. For the treatment of spasticity, onabotulinumtoxinA is injected directly into affected muscles. Intramuscular injections may result in local bleeding and related complications, especially in patients receiving anticoagulant therapy. Despite anticoagulants being commonly used, there is limited information in the medical literature regarding the safety of intramuscular medications in patients receiving oral anticoagulants. This retrospective analysis included pooled safety data from Allergan-sponsored studies evaluating onabotulinumtoxinA for the treatment of patients with muscle spasticity.ObjectiveThe objective of this study was to determine the risk of bleeding complications in patients with post-stroke spasticity receiving antithrombotic therapy and intramuscular onabotulinumtoxinA.MethodsWe conducted a retrospective analysis of pooled safety data from 16 randomized, double-blind, placebo-controlled Allergan-sponsored studies of onabotulinumtoxinA for the treatment of post-stroke upper or lower limb muscle spasticity, including adult patients with at least moderate upper or lower limb spasticity and receiving at least one dose of the study drug. Bleeding-related adverse events starting within 4 weeks of study treatment were assessed. The incidence rates of bleeding complications were compared for patients receiving classes of antithrombotic therapy vs those not receiving antithrombotic therapy and for those receiving onabotulinumtoxinA vs placebo (with or without antithrombotic therapy).ResultsOf 1877 patients, 1182 received antithrombotic therapy. The overall incidence of bleeding complications was < 2%. In those receiving any antithrombotic therapy, the incidence of bleeding was 1.0% vs 1.4% (no antithrombotic therapy); after onabotulinumtoxinA, it was 0.9% for those receiving antithrombotic therapy vs 1.4% (no antithrombotic therapy), and for placebo 1.2% vs 1.4%, respectively. Subgroup results were similar.ConclusionsNo apparent increased risk of bleeding complications was observed following administration of onabotulinumtoxinA to patients receiving antithrombotic therapy. Nonetheless, patient education and careful observation of the injection site in patients receiving antithrombotic therapy remains warranted.

A Meta-Analysis Evaluating the Risk of Bleeding-Related Adverse Events with Defibrotide Treatment

<h3>Introduction</h3> Defibrotide (DF) is approved for adult and pediatric patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) with renal or pulmonary dysfunction after hematopoietic cell transplantation (HCT) in the United States. The recommended dose is 6.25 mg/kg every 6 hours given as a 2-hour intravenous (IV) infusion. <i>In vitro</i>, DF reduces activation of endothelial cells, promotes fibrinolytic enzymes, and exhibits antithrombotic properties. Post-HCT patients with VOD/SOS are often at a high risk for bleeding events. <h3>Objectives</h3> To broaden our understanding of the potential risk of bleeding events with DF treatment, this meta-analysis assessed the incidence and risk of bleeding-related AEs with DF outside of the VOD/SOS and HCT setting, using published literature. <h3>Methods</h3> PubMed and Embase were searched through July 24, 2018 for studies using DF. Studies of patients with VOD/SOS or HCT, case reports with <10 patients, and reviews were excluded. Publications containing data on bleeding-related events were included. Overall bleeding rate and risk ratio of bleeding were calculated from studies that used IV DF. The Freeman-Tukey double arcsine transformation and random-effects modeling (Stata Software) and the Mantel-Haenszel method and random-effects modeling (RevMan 5.3 Software) were used for overall bleeding rate and risk ratio, respectively. <h3>Results</h3> A total of 1,857 records were identified; 125 studies reported on DF and 23 contained data on bleeding and were included in the analysis. Most studies (17 of 23) had 2 treatment arms; among these, heparin was the most common comparator (14 of 17). Overall, 14 of 23 studies used IV DF; the most commonly administered dose was 800 mg daily and IV DF was used to treat deep vein thrombosis (10 studies), acute myocardial infarction (2 studies), thrombosis (1 study), and "other" (1 study). The bleeding rate and risk ratio of bleeding were calculated using data from the 14 IV DF studies only. Rates of bleeding events from the 14 studies with IV DF ranged from 0% to 10% in individual studies; the estimated overall bleeding rate was 1% (95% confidence interval [CI]: 0.00-0.02). Among 10 studies with available data on IV DF and controls (8 calcium heparin, 1 urokinase, 1 conventional supportive treatment), the risk ratio for bleeding events with IV DF versus controls was 0.36 (95% CI: 0.24-0.52; <i>P</i> <0.00001; Figure). <h3>Conclusion</h3> This meta-analysis showed that the risk of bleeding with DF was low in patients outside of the VOD/SOS setting, and there is comparable risk of bleeding with DF treatment versus controls such as heparin or urokinase. Limitations of this analysis include variations in AE reporting across studies and the use of a DF dose that is lower than the currently approved recommended dose.

Functionally Significant Coumarin-Related Variant Alleles and Time to Therapeutic Range in Chilean Cardiovascular Patients.

Despite the development of new oral agents over the last decade, vitamin K antagonists (VKAs) remain the most widely used anticoagulants for treating and preventing thromboembolism worldwide. In Chile, the Ministry of Health indicates that acenocoumarol should be used in preference to any other coumarin. Complications of inappropriate dosing are among the most frequently reported adverse events associated with this medication. It is well known that polymorphisms in pharmacokinetic and pharmacodynamic proteins related to coumarins (especially warfarin) influence response to these drugs. This work analyzed the impact of CYP2C19*2 (rs4244285), CYP1A2*1F (rs762551), GGCx (rs11676382), CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), CYP4F2 (rs2108622), VKORC1 (rs9923231), VKORC1 (rs7294), CYP3A4*1B (rs2740574), and ABCB1 (rs1045642) polymorphisms on time to therapeutic range for oral anticoagulants in 304 Chilean patients. CYP2C9*3 polymorphisms were associated with time to therapeutic range for acenocoumarol in Chilean patients, and the CYP4F2 TT genotype, MDR1 A allele, CYP1A2 A allele, and CYP3A4T allele are promising variants that merit further analysis. The presence of polymorphisms explained only 4.1% of time to therapeutic range for acenocoumarol in a multivariate linear model. These results improve our understanding of the basis of ethnic variations in drug metabolism and response to oral anticoagulant therapy. We hope that these findings will contribute to developing an algorithm for VKA dose adjustment in the Chilean population in the near future, decreasing the frequency of stroke, systemic embolism, and bleeding-related adverse events.

Safety of Caplacizumab in Patients Without Documented Severe ADAMTS13 Deficiency During the HERCULES Study

Safety of Caplacizumab in Patients Without Documented Severe ADAMTS13 Deficiency During the HERCULES Study

A Meta-Analysis Evaluating the Risk of Bleeding-Related Adverse Events with Defibrotide Treatment

Introduction: Defibrotide is approved for adult and pediatric patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) with renal or pulmonary dysfunction after hematopoietic cell transplantation (HCT) in the United States and Canada and for patients aged &gt;1 month with severe hepatic VOD/SOS post-HCT in the European Union. The recommended dose is 6.25 mg/kg every 6 hours given as a 2-hour intravenous (IV) infusion. Defibrotide has been shown in vitro to reduce endothelial cell (EC) activation and promote EC-mediated fibrinolysis. Post-HCT patients with VOD/SOS are often at a high risk for bleeding events. In a phase 3 study of patients with VOD/SOS post-HCT, rates of bleeding-related adverse events (AEs) with defibrotide were generally similar to matched historic controls (Richardson PG, et al. Blood. 2016;127[13]:1656-1665). To broaden our understanding of the risk of bleeding events associated with defibrotide treatment, this meta-analysis assessed the incidence and risk of bleeding-related AEs with defibrotide treatment in studies outside of the VOD/SOS and HCT setting, using published literature. Methods: PubMed and Embase were searched from database inception through July 24, 2018 for studies using defibrotide (controlled trials with ≥1 arm assessing an intervention of interest, observational/retrospective studies, retrospective or post hoc analyses, and case series with ≥10 patients). Studies of patients with VOD/SOS or HCT, case reports with &lt;10 patients, and reviews were excluded. Publications were evaluated for the presence of data on endpoints of interest, which included any bleeding-related event and overall safety or efficacy summaries; all studies with available data were included in the analysis. Overall bleeding rate was estimated for defibrotide and controls using the Freeman-Tukey double arcsine transformation and random-effects modeling (Stata Software). The risk ratio of bleeding was calculated using the Mantel-Haenszel method and random-effects modeling (RevMan 5.3 Software). Overall bleeding rate and risk ratio of bleeding were calculated from studies that used the IV defibrotide formulation; studies using oral or intramuscular formulations were excluded from these calculations. Results: A total of 1,857 records were identified in the search; 124 studies reported on defibrotide and 19 contained data related to bleeding and were included in the analysis. Of the 19 included studies, 2 had &gt;1,000 patients. An IV defibrotide formulation was used in 12 studies; the other 7 used intramuscular or oral delivery or more than one method of defibrotide administration. The most common indications were prevention of deep vein thrombosis (11 of 19) and treatment of thrombosis (3 of 19). Most studies (14 of 19) had 2 treatment arms; among these studies, heparin was the most common comparator (11 of 14). For the other 5 of 19 studies, 4 studies were single-arm and 1 study had 3 arms. The majority of studies (16 of 19) were conducted in adults; the other 3 studies did not specify patients' age. The most commonly administered defibrotide dose was 800 mg daily (14 of 19 studies). Bleeding rate and risk ratio of bleeding were calculated based upon data from the 12 studies that used IV defibrotide. Rates of bleeding events reported in the 12 studies with IV defibrotide ranged from 0% to 10% in individual studies and the estimated overall bleeding rate was 1% (95% confidence interval [CI]: 0.00-0.03). In 10 studies with control treatments (9 calcium heparin, 1 urokinase), rates of bleeding events ranged from 1% to 37%, with 7 studies having rates ≥10%. Across the 10 control studies, the estimated overall bleeding rate for controls was 11% (95% CI: 0.05-0.20). Among the 8 studies with available data on IV defibrotide and controls (7 calcium heparin, 1 urokinase), the risk ratio for bleeding events with IV defibrotide versus controls was 0.36 (95% CI: 0.24-0.52; P &lt;0.00001; Figure). Conclusions: This meta-analysis of defibrotide use outside of the VOD/SOS setting suggests that the bleeding risk with defibrotide is low, and there is comparable risk of bleeding with defibrotide treatment versus controls such as heparin or urokinase. Important limitations of this analysis include variations in AE reporting across studies and the use of a defibrotide dose that is lower than the currently approved recommendation in the majority of studies. Disclosures Tappe: Jazz Pharmaceuticals: Employment, Equity Ownership. Aggarwal:Jazz Pharmaceuticals: Consultancy. Topaloglu:Jazz Pharmaceuticals: Consultancy. Iacobelli:Massimo Iacobelli: Consultancy. OffLabel Disclosure: The abstract describes a meta-analysis of defibrotide (indicated for VOD/SOS) in the non-VOD/SOS setting. As this analysis drew data from existing literature, no patients were administered defibrotide for off-label indications in the course of this analysis.

947 Lusutrombopag for Treatment of Thrombocytopenia in Patients With Chronic Liver Disease Who Are Undergoing Planned Invasive Procedures: Pooled Safety Analysis of Bleeding-Related Adverse Events

INTRODUCTION: Thrombocytopenia is a common complication in patients with chronic liver disease. A low platelet count in chronic liver disease patients who require an invasive procedure is a serious condition that may be associated with an increased risk of bleeding during or after the procedure. Lusutrombopag is a thrombopoietin receptor agonist approved in Japan (2015) and the US (2018) for treatment of thrombocytopenia, and in the EU (2019) for severe thrombocytopenia, associated with chronic liver disease in patients undergoing a planned invasive procedure. A pooled safety analysis was performed to assess differences in bleeding events following treatment with lusutrombopag without platelet transfusion or placebo with platelet transfusion. METHODS: Safety data were pooled from 3 double-blind, placebo-controlled studies, in patients with thrombocytopenia associated with chronic liver disease undergoing a planned invasive procedure (Phase 2b: M0626 [Japan; JapicCTI-121944]; Phase 3: L-PLUS 1 [Japan; JapicCTI-132323], L-PLUS 2 [global; NCT02389621]). Patients enrolled in these studies were randomized to lusutrombopag 3 mg or placebo for up to 7 days prior to procedure. Platelet transfusion was administered if platelet count was &lt; 50 × 109/L no more than 2 days prior to procedure. Patients were classified into 1 of 4 subgroups: lusutrombopag alone or +platelet transfusion or placebo alone or +platelet transfusion. This analysis focused on patients in the lusutrombopag alone and placebo + platelet transfusion subgroups. Bleeding events were summarized pre-, during, and post-procedure. RESULTS: Lower bleeding event rates, regardless of severity and timing of onset, were observed for lusutrombopag alone vs placebo + platelet transfusion (Table 1). Percent of patients with bleeding events was numerically higher with placebo + platelet transfusion vs lusutrombopag alone, both during (4.8% vs 3.2%) and post-procedure (7.1% vs 4.0%). Percent of patients with procedural and post-procedural bleeding events in liver-related procedures was greater in the placebo + platelet transfusion (16.1%) vs lusutrombopag alone (11.1%) arm, and a larger difference was seen with gastrointestinal-related procedures in the placebo + platelet transfusion (8.9%) vs lusutrombopag alone (2.0%) arm. CONCLUSION: In this pooled analysis, a trend toward lower bleeding event rates was observed with lusutrombopag alone vs placebo + platelet transfusion, regardless of type of invasive procedure.

Caplacizumab in acquired thrombotic thrombocytopenic purpura: a profile of its use

Caplacizumab (Cablivi™), an anti-von Willebrand factor Nanobody®, is indicated for the treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), in conjunction with plasma exchange and immunosuppression. When combining the results of phase 2 and 3 trials in patients with aTTP, caplacizumab reduced the time to normalization of platelet count compared with placebo, and was associated with reductions in the rate of aTTP-related death, aTTP recurrence or a major thromboembolic event. Although caplacizumab was associated with more bleeding-related adverse events than placebo, most of these events were of mild or moderate severity and did not require therapeutic intervention.