scholarly journals Athn 15: Characterizing the Real-World Use of Direct Oral Anticoagulants in Pediatric Patients - Interim Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-20
Author(s):  
Jennifer G. Davila ◽  
Fernando F. Corrales-Medina ◽  
Dunlei Cheng ◽  
Leslie J. Raffini ◽  
Courtney D Thornburg ◽  
...  
Keyword(s):  
Real World ◽  
Research Funding ◽  
Pediatric Patients ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Safety Monitoring ◽  
Data Safety Monitoring Board ◽  
Advisory Board ◽  
The Real ◽  
The Us

Background: There are currently four direct oral anticoagulants (DOACs) approved for the acute treatment and prevention of venous thromboembolism (VTE) in adults. Pediatric hematologists across the United States (US) are using DOACs for their patients based on extrapolated data from adult studies and recently published phase 3 pediatric-specific studies. (Brandao LR, et al. Blood, 2019 and Male C, et al. Lancet Haematol, 2020.) Because further data regarding DOAC use in children are needed, ATHN 15: Characterizing the Real-World Use of Direct Oral Anticoagulants in Pediatric Patients, was developed and is being sponsored by the American Thrombosis and Hemostasis Network (ATHN). The study is being conducted at ATHN-affiliated sites in the US and aims to characterize the real-world use of DOACs in children diagnosed with VTE. ATHN is a nonprofit network of over 140 federally funded hemophilia treatment centers (HTCs) that provides the infrastructure for clinical research and public health surveillance. Methods: Data being captured includes demographics, clinical characteristics, anticoagulation management, and treatment outcomes (bleeding and recurrent thrombosis) of patients <21 years of age, who have received or are receiving a DOAC since January 1, 2015 for the treatment of an acute VTE episode or prevention of thrombosis recurrence. Data are collected for up to 6 months from the start of DOAC treatment. Results: As of May 31, 2020, 76 patients from 9 sites have been enrolled (see Table 1 for demographics). Deep venous thrombosis (DVT) of the lower extremities or pelvis is the most prevalent VTE (n = 23, 30.26%), followed by DVT of the upper extremity or upper thorax and pulmonary embolism plus VTE (n = 22, 28.95 and n = 13, 17.1% respectively). 82.89% of patients did not have a history of prior VTE at the time of enrollment. Of the 15 patients with a radiologically confirmed anatomic anomaly, Paget Schroetter/Thoracic Outlet Syndrome and May-Turner Syndrome are the most common (n = 6, 40% and n = 4, 26.7%, respectively). Factor V Leiden heterozygosity, reported in 8 patients, is the most prevalent inherited thrombophilia. Forty-eight patients were identified as having a medical risk factor associated with their VTEs. Sixteen (33.3%) were classified as obese and another 13 (27.1%) had a hospital admission stay greater than 7 days and within 30 days prior to the VTE. At least one specific drug or environmental risk factor was reported in 44 patients. Concomitant use of hormonal contraception (currently taking/stopped within 4 weeks prior to VTE) and the presence of a central venous catheter (present at time of VTE or within 30 days prior to VTE) were the most commonly reported (n = 18, 40.9% and n = 15, 34.09%, respectively). Rivaroxaban is the most prescribed DOAC with 59.2% (n = 45) of patients using this agent. Apixaban and dabigatran use is also reported (n = 29; 38.2% and n = 2; 2.6% respectively). Of the 76 patients, 65 received a different anticoagulant prior to starting a DOAC. Enoxaparin and unfractionated heparin are most commonly prescribed prior to the institution of a DOAC regimen (n = 52, 80% and n = 17, 26.2%). Conclusions: Despite lack of an FDA-approved pediatric indication, hematologists in the US are already using DOACs for children with VTE. Most pediatric patients treated with a DOAC are older than 13 years of age, although we anticipate this will change as providers develop more comfort with these drugs. Interestingly, most of these patients were started on a different anticoagulation regimen prior to starting a DOAC. As enrollment continues, ATHN 15 will serve as a resource for pediatric hematologists to characterize the real-world use of DOACs in children. Further analysis will evaluate DOAC-specific utilization, efficacy and adverse events, including heavy menstrual bleeding. Disclosures Davila: Spire Learning: Speakers Bureau; ATHN: Other: Grant Funding. Corrales-Medina:Bayer: Consultancy; Takeda: Consultancy; Octapharma: Consultancy, Speakers Bureau. Raffini:XaTek: Other: Advisory Board; CSL Behring: Other: Advisory Board; HemaBiologics: Other: Advisory Board; Bayer: Other: Advisory Board; Roche: Other: Advisory Board. Thornburg:Sanofi Genzyme: Consultancy, Other: Data Safety Monitoring Board, Research Funding; NovoNordisk: Research Funding; Genentech: Speakers Bureau; Biomarin: Consultancy, Speakers Bureau; Bayer Pharmaceuticals: Research Funding; American Thrombosis and Hemostasis Network: Research Funding; National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ironwood Pharmaceuticals: Consultancy, Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Spark Therapeutics: Consultancy. OffLabel Disclosure: Apixaban, Rivaroxaban, Dabigatran and Enoxaparin use in the pediatric population.

Do the Safety and Efficacy Outcomes Reported in the Clinical Trials of Direct Oral Anticoagulants (DOAC) Translate to the Real-World?

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2335-2335
Author(s):  
Shammim Haji ◽  
Jignesh P Patel ◽  
Vivian Auyeung ◽  
Lara N Roberts ◽  
Julia Czuprynska ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Major Bleeding ◽  
Real World ◽  
Research Funding ◽  
Oral Anticoagulants ◽  
Phase Iii ◽  
World Population ◽  
Safety And Efficacy ◽  
The Real ◽  
Pooled Data

Abstract Do the safety and efficacy outcomes reported in the clinical trials of direct oral anticoagulants (DOAC) translate to the 'real-world'? Background: A number of DOACs are now available for clinicians to prescribe in clinical practice. Whilst the results from large clinical trials demonstrate that these agents are as effective as vitamin K antagonists, there is some concern that the patients studied in the trials were not representative of patients, clinicians encounter in everyday practice. The aim of our study was to compare the real-world clinic population commenced on a DOAC to that from the clinical trials for these agents, in order to assess potential differences in safety and efficacy. Patients and methods: A retrospective observational cohort study was undertaken. Patients who were initiated on a DOAC (apixaban, dabigatran and rivaroxaban) at a large teaching hospital in South East London between 1st August 2012 and 31st July 2014 were identified through pharmacy issue data with those followed-up for a minimum of 6 months included. Baseline demographic data, rates of stroke/VTE and rates of major/non-major clinically relevant (NMCR) (ISTH definition) bleeding were assessed and compared to pooled data reported from the corresponding Phase III trials. Differences between groups were compared using t-tests or chi-squared tests. Results: During the review period, 748 patients were initiated on a DOAC, 365 for atrial fibrillation (AF) and 383 for venous thromboembolism (VTE). In terms of demographic differences, the real-world AF population comprised more females, were significantly older, had poorer renal function and a lower body weight. In contrast, the real-world VTE population typically had a higher body weight and poorer renal function, compared to the trial population, (table 1). Efficacy of DOACs was found to be similar across both the VTE and AF populations. With respect to safety, the real-world AF population experienced similar rates of major bleeding and a significantly lower rate of NMCR bleeding compared to the trial populations. In contrast, the real-world VTE population experienced a significantly higher rate of major bleeding, particularly gastrointestinal bleeding. Although the rate of NMCR bleeding was similar, there was a significantly higher rate of urogenital bleeding in the real-world VTE population, specifically heavy menstrual bleeding in women. Conclusions: The efficacy outcomes of DOAC use in a real-world AF and VTE population are consistent with the Phase III trials, despite some significant differences in baseline characteristics. However, a significantly increased rate of major bleeding was observed in the real-world VTE population, which requires further investigation. Table 1. Baseline demographic characteristics, efficacy and safety outcomes in the real-world population versus the trial population Atrial Fibrillation Venous Thromboembolism Trial population+N=28,342 Real-world population Trial population++ Real-world population N=365 N=8,716 N=383 Baseline Demographics, mean (SD) unless otherwise specified Age, years 72 (9.6) 76.8 * (12.1) 56.9 (14.2) 55.6 (18.7) Female (%) 10451 (36.9) 215 * (58.9) 3753 (43.1) 184 (48.0) Weight, kg 82.7 (19.5) 77.3 * (22.6) 84.9 (19.6) 88.2 * (23.0) Creatinine clearance, mL/min 69 (26.7) 58.1 * (26.9) 105.8 (40.7) 91.1 * (37.6) Concomitant aspirin therapy 10341 (36.5) 49 * (13.4) - 0 (0) Previous VKA use (%) 15711 (55.4) 193 (52.9) - 85 (22.2) Efficacy (%) All-cause mortality 1695 (6.0) 37 * (9.1) 160 (1.8) 10 (2.5) Stroke 676 (2.4) 8 (2.0) - 1 (0.3) VTE 39 (0.1) 1 (0.2) 192 (2.2) 7 (1.8) Safety (%) Major Bleeding 1419 (5.0) 17 (4.2) 79 (0.9) 15 * (3.8) Intracranial 170 (0.6) 1 (0.2) 6 (0.1) 2 * (0.5) Gastrointestinal 644 (2.3) 8 (2.0) 8 (0.1) 8 * (2.0) Non-major Clinically relevant (NMCR) bleeding 4824 (17.0) 30 * (7.4) 540 (6.2) 26 (6.6) Gastrointestinal - 9 (2.2) 53 (4.2) 10 (2.5) Urogenital 296 (4.2) 16 (3.9) 100 (2.5) 38 * (9.6) +Pooled data from ARISTOTLE, RE-LY and ROCKET-AF trials ++Pooled data from AMPLIFY, RE-COVER and EINSTEIN-PE/DVT trials *p<0.05 Disclosures Patel: Bayer plc: Research Funding. Auyeung:Bayer PLC: Research Funding. Arya:Bayer plc: Research Funding.

scholarly journals MCL-1 and PKA/AMPK Axis Fuel Venetoclax Resistance in Lymphoid Cancers

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1284-1284
Author(s):  
Vivian M. Liu ◽  
Romain Guièze ◽  
Daniel Rosebrock ◽  
Alexis A Jourdain ◽  
María Hernández-Sánchez ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Board Of Directors ◽  
Cell Lines ◽  
Research Funding ◽  
Safety Monitoring ◽  
Data Safety Monitoring Board ◽  
Advisory Board ◽  
Advisory Committees ◽  
Data Safety ◽  
Genome Wide

Venetoclax, the first approved BH3 mimetic targeting BCL2, demonstrates high response rate in chronic lymphocytic leukemia (CLL) but resistant cases are emerging. Aside from BCL2 mutations affecting venetoclax binding, multiple lines of mounting evidence suggest a role for non-mutational mechanisms underlying resistance to this drug. By applying both CRISPR-Cas9 knock-out and ORF overexpression screens in the lymphoma cell line OCI-Ly1, we previously reported the identification of MCL-1 overexpression and of the AMPK/PKA signaling axis in altering energy metabolism underlying venetoclax resistance (Guieze, ASH 2018). Here, we report further in-depth exploration of the impact of these findings, discovered through the analysis of lymphoid cell lines, and of specimens collected from CLL patients developing venetoclax resistance. The resistant lymphoma cell lines that we generated (OCI-Ly1 and SU-DHL4 cells) displayed increased oxidative phosphorylation (OXPHOS) compared to the parental lines, measured by Seahorse assay. We instead observed that venetoclax rapidly perturbs OXPHOS in sensitive cells. This process is dependent on mitochondrial outer membrane permeabilization, as this effect is abrogated in BAX/BAK1 double knockout (KO) cells. Targeting OXPHOS was shown to synergize with venetoclax in vitro and in vivo, as combination of venetoclax and oligomicin (an inhibitor of the ATP synthase, the complex V of the mitochondrial electron transport chain), was more effective than each drug alone in reducing tumor growth of a subcutaneous NSG xenograft model based on OCI-Ly1. Among the candidate markers driving resistance identified from the genome-wide screens, we focused on AMP pathway members (AMPK and PKA) and the ID3 transcriptional regulator, given that ID3 KO cells demonstrated similar transcriptomic changes than the resistant OCI-Ly1 cells. We found that PRKAR2B (encoding a PKA subunit), already highlighted in our ORF screen, was the top transcript overexpressed when knocking out ID3. To clarify how the dominant-negative transcription factor ID3 regulates PRKAR2B expression, we performed ATAC-seq of the ID3 OCI-Ly1 knockout (vs control) lines in order to determine differential signatures of chromatin accessibility and transcription factor engagement. We showed that ID3 repression leads to genome-wide increased accessibility associated with motifs of the lymphoid transcription factor TCF3. TCF3 has previously been shown to interact with ID3 and to be involved in the transcription of ADIPOQ, which was identified in the GOF screen. TCF3 binding sites were confirmed to be present within putative enhancer regions of PRKAR2B in a B cell context. We then investigated whether our findings could be validated in patient samples. By whole-exome sequencing of matched pretreatment and venetoclax-resistant CLL samples collected from 6 patients, we did not detect any recurrent somatic mutations associated with resistance. The resistant samples from three of 6 patients, however, harbored subclones with 1q amplification in a common region encompassing the MCL1 locus. We identified 4 additional CLL cases relapsing on venetoclax with leukemia samples collected before and after relapse. By immunohistochemical staining of 9 of 10 cases for which tissue was available, we detected increased MCL-1 expression at relapse in 6 of 9 cases (p = 0.026). We furthermore confirmed the involvement of AMPK signaling by detecting evidence of AMPK, ACC and p-ACC expression in 4 of 9 patients (all p = 0.0062). ID3 expression was decreased at matched relapse samples (p = 0.0001), supporting the presence of the resistance circuit we identified above. Taken together, our results identified the increased MCL-1 expression and PKA/AMPK activation as underlying mechanisms for venetoclax resistance. Our data support the implementation of combinatorial therapy with metabolic modulators to address venetoclax resistance. Disclosures Guièze: Abbvie: Honoraria; Roche: Honoraria; Janssen: Honoraria; Gilead: Honoraria. Thompson:AbbVie: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Davids:AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding. Brown:AbbVie: Consultancy; Acerta Pharma: Consultancy; Loxo: Consultancy, Research Funding; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria; Teva: Honoraria; Morphosys: Other: Data safety monitoring board; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Juno/Celgene: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding. Wierda:Xencor: Research Funding; Cyclcel: Research Funding; Genentech: Research Funding; Pharmacyclics LLC: Research Funding; Gilead Sciences: Research Funding; KITE pharma: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Sunesis: Research Funding; AbbVie: Research Funding; Janssen: Research Funding; Acerta Pharma Inc: Research Funding; GSK/Novartis: Research Funding; Miragen: Research Funding; Loxo Oncology Inc.: Research Funding; Juno Therapeutics: Research Funding. Letai:AbbVie, AstraZeneca, Novartis: Consultancy, Research Funding; Zeno Pharmaceuticals, Vivid Bioscience, Flash Therapeutics, Dialectic Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Cofounder or Advisory Board member. Neuberg:Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Equity Ownership; Celgene: Research Funding. Mootha:Jansen Pharmaceuticals: Other: SAB, compensation; 5am Ventures: Other: SAB, compensation; Raze Therapeutics: Other: Founder, SAB, equity. Getz:MuTect, ABSOLTUE, MutSig and POLYSOLVER: Patents & Royalties: MuTect, ABSOLTUE, MutSig and POLYSOLVER; Pharmacyclics: Research Funding; IBM: Research Funding. Wu:Pharmacyclics: Research Funding; Neon Therapeutics: Other: Member, Advisory Board.

scholarly journals Thrombotic and Bleeding Outcomes Following Perioperative Interruption of Direct Oral Anticoagulants and Vitamin K Antagonists in Patients with Non-Valvular Atrial Fibrillation - a Comparative Analysis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1234-1234
Author(s):  
Joseph R. Shaw ◽  
Tinghua Zhang ◽  
Gregoire Le Gal ◽  
James Douketis ◽  
Marc Carrier
Keyword(s):  
Major Bleeding ◽  
Research Funding ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Bleeding Risk ◽  
Advisory Board ◽  
Bleeding Events ◽  
Chads2 Score ◽  
High Bleeding Risk

Abstract Background: Atrial fibrillation (AF) is a common disorder that will affect up to 5.6 million patients in the U.S. by 2050. Both direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs), typically warfarin, are used for stroke prevention in AF and such patients frequently undergo invasive procedures requiring anticoagulant interruption. Temporary interruption of anticoagulants can be associated with significant morbidity and mortality in the form of thromboembolic and bleeding complications. DOACs have a short half-life and fast onset of action, thereby facilitating their perioperative management as compared to VKAs. Despite important differences in perioperative management and pharmacokinetics between DOACs and VKAs, there is a paucity of data comparing perioperative outcomes in DOAC and VKA-treated patients. Methods: We undertook a single-center, retrospective chart review that compared consecutive DOAC- or warfarin-treated patients with AF who underwent perioperative anticoagulant interruption for invasive procedures between January 2017 and March 2018. Perioperative warfarin interruption was done as per CHEST guidelines (Douketis et al. Chest 141,2 Suppl). Perioperative bridging with low-molecular-weight heparin was only used for patients with CHADS2 scores of 5-6 or in patients with stroke within the past 6 months. Perioperative interruption of DOACs was done as per Thrombosis Canada guidelines, with anticoagulation held for 3 half-lives prior to low bleeding risk procedures and 5 half-lives for high bleeding risk procedures. Primary outcomes included the 30-day post-operative thromboembolic and major bleeding rates. Secondary outcomes included the 30-day clinically relevant non-major bleeding (CRNMB) andl mortality rates. Major bleeding and CRNMB were defined according to ISTH definitions. Procedural bleeding risk was defined as per Schulman et al (Circulation 2015; 132(3)). Outcome events were independently adjudicated by two investigators. Outcomes from patients on DOACs and VKAs were compared. Demographic data was analyzed on a per-patient basis, p-values were calculated using independent T-Test, Chi-Square/Fisher's Exact Test where appropriate. Outcome data was analyzed on a per-interruption basis. P-values for unadjusted and adjusted comparisons were calculated using generalized estimating equations (GEE) to account for correlation between multiple procedures on the same patients. Results: 325 DOAC patients and 199 warfarin patients underwent 351 and 221 periprocedural interruptions, respectively. Warfarin patients had a significantly higher mean age, CHADS2 score, and proportion with renal dysfunction (Table 1). There was no statistically significant difference in 30-day post-operative rates of thromboembolism, CRNMB, and overall mortality, but warfarin patients had a significantly higher rate of major bleeding (Table 2). This latter result remained statistically significant following multivariate logistic regression correction for age, CHADS2 score and level of renal dysfunction. All bleeding events occurred post-procedure, with major bleeding events occurring from post-operative day 1 to post-operative day 25. None of the warfarin patients with major bleeding received perioperative bridging; the mean international normalized ratio (INR) at the time of major bleeding was 3.3. Most major bleeding events (7/8) in the VKA arm were surgical, with a single non-surgical major-bleed (spontaneous ICH on post-operative day 15 following urological surgery). Conclusions: The perioperative interruption of warfarin was associated with a higher 30-day rate of major bleeding as compared with DOAC interruption. Re-initiation of warfarin should be done judiciously following high bleeding risk procedures, and close INR monitoring may be warranted. Disclosures Shaw: Portola Pharmaceuticals: Research Funding. Douketis:Janssen: Consultancy; Pfizer: Other: Advisory Board; Boehringer-Ingelheim: Consultancy, Other: Advisory Board, Research Funding; Portola: Other: Advisory Board; The Medicines Company: Other: Advisory Board; Daiichi-Sankyo: Other: Advisory Board; Biotie: Other: Advisory Board; Bayer: Other: Advisory Board; Sanofi: Consultancy, Other: Advisory Board; BMS: Other: Advisory Board; Astra-Zeneca: Other: Advisory Board. Carrier:Bayer: Honoraria; Pfizer: Honoraria; BMS: Honoraria, Research Funding; Leo Pharma: Research Funding.

scholarly journals Real-World Clinical Outcomes in Previously Untreated and Minimally Treated Patients with Congenital Factor VIII Deficiency: The San Diego Experience

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 31-32
Author(s):  
Kelly A Bush ◽  
Hilda Ding ◽  
Kate O'Flaherty-Keese ◽  
Rosalie Brooks ◽  
Katharine Farrow ◽  
...  
Keyword(s):  
Factor Viii ◽  
Real World ◽  
Research Funding ◽  
Adverse Reactions ◽  
High Titer ◽  
Safety Monitoring ◽  
Data Safety Monitoring Board ◽  
Data Safety ◽  
On Demand ◽  
Fviii Inhibitor

Introduction: Emicizumab is a bi-specific, humanized, monoclonal antibody that mimics the function of activated Factor VIII (FVIII). It is approved for prophylaxis in persons of all ages with hemophilia A (HA) both with and without a FVIII inhibitor. The data on the use of emicizumab in previously untreated patients (PUPs) and minimally treated patients (MTPs) are scarce, with only one PUP reported in the pediatric clinical trials for the drug. The objective of this retrospective study was to describe our real-world institutional experience in prescribing emicizumab prophylaxis for PUPs and MTPs. Methods: This analysis includes six patients between 1-23 months of age with severe HA prescribed emicizumab prophylaxis at Rady Children's Hospital San Diego (RCHSD) Hemophilia and Thrombosis Treatment Center between November 2017 to April 2020. Data collected through April 2020 included demographics, inhibitor history, bleeding and treatment history prior to initiation of emicizumab prophylaxis, reason for initiation of emicizumab, age, weight, and dosing regimen at the beginning of emicizumab prophylaxis, bleeding and surgical history after initiation of emicizumab, and adverse reactions to emicizumab. Results: Our cohort of six patients included 1 PUP and 5 MTPs with less than 20 FVIII exposure days (ED) prior to the initiation of emicizumab prophylaxis. All MTPs patients were previously treated with on-demand treatment prior to the initiation of emicizumab. Demographic and clinical characteristics are shown in Table 1. The median age and weight at initiation of emicizumab were 8 months (range: 1 to 23 months) and 9.5 kg (range: 4.4 to 11.8 kg) respectively. One patient who was treated on-demand was diagnosed with a high-titer FVIII inhibitor in the setting of a mouth bleed and started emicizumab prophylaxis after bleed management. The most common reason for initiation of emicizumab prophylaxis in non-inhibitor patients was the ability to administer medication without reliable venous access. Following four once weekly loading doses with emicizumab, five patients continued weekly maintenance dosing and one patient continued every 28 day maintenance dosing. Patients were followed for a median of 9 months (range 3-24 months) after emicizumab initiation. Four patients, including the patient with a known FVIII inhibitor prior to starting emicizumab, had zero treated bleeds following initiation of emicizumab prophylaxis. Two patients were diagnosed with high-titer FVIII inhibitors on routine inhibitor surveillance after initiation of emicizumab prophylaxis and were the only patients who experienced treated bleeds during the study period. The majority (6 of 8) of treated bleeds were traumatic. The patient with the highest FVIII inhibitor titer experienced a disproportionately high number of the total treated bleeds though three of the seven bleeds were prior to FVIII inhibitor diagnosis. No patients required central venous catheter placement. One patient underwent circumcision with peri-operative FVIII replacement and did not have post-op bleeding. In terms of medication safety, one patient reported injection site bruising. No patient experienced severe adverse reactions including thrombotic microangiopathy, thrombosis, or clinical evidence of anti-drug neutralizing antibodies. All patients continued emicizumab prophylaxis during the study period. Conclusions: We found that prophylaxis with emicizumab is efficacious and well-tolerated in our cohort of young children with HA under the age of 24 months both with and without high-titer FVIII inhibitors. Two patients were diagnosed with high-titer FVIII inhibitors on routine surveillance after initiation of emicizumab prophylaxis, which highlights the importance of continuing FVIII inhibitor surveillance after initiation of emicizumab. More data are needed on the use of emicizumab, particularly in PUPs and MTPs, with regards to safety, efficacy, and prevention of inhibitors in this patient population. Disclosures Thornburg: American Thrombosis and Hemostasis Network: Research Funding; National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharmaceuticals: Research Funding; Biomarin: Consultancy, Speakers Bureau; Genentech: Speakers Bureau; NovoNordisk: Research Funding; Sanofi Genzyme: Consultancy, Other: Data Safety Monitoring Board, Research Funding; Spark Therapeutics: Consultancy; Bluebird Bio: Consultancy; Ironwood Pharmaceuticals: Consultancy, Other: Data Safety Monitoring Board.

scholarly journals Characterizing the Use of Direct Oral Anticoagulants in Children Using the American Thrombosis and Hemostasis Network Dataset (ATHNdataset)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1156-1156
Author(s):  
Jennifer G. Davila ◽  
Dunlei Cheng ◽  
Leslie J. Raffini ◽  
Courtney D. Thornburg ◽  
Fernando F. Corrales-Medina
Keyword(s):  
Venous Thrombosis ◽  
Board Of Directors ◽  
Research Funding ◽  
Safety Monitoring ◽  
Data Safety Monitoring Board ◽  
Advisory Board ◽  
Advisory Committees ◽  
Data Safety ◽  
Safety Monitoring Board ◽  
Data Safety Monitoring

Background: The incidence of venous thromboembolism (VTE) in children has risen significantly. (Raffini, Huang et al. 2009) There are currently four direct oral anticoagulants (DOACs) - apixaban, dabigatran, edoxaban, and rivaroxaban - approved for the acute treatment and prevention of VTE in adults. Advantages of these medications over the traditionally used anticoagulants, enoxaparin and warfarin, include fixed dosing, no need for routine laboratory monitoring, few drug interactions and no dietary restrictions. Despite lack of information on the safety and efficacy of these agents in children, pediatric hematologists across the United States are using DOACs in their patients based on extrapolated data from adult studies. The American Thrombosis and Hemostasis Network (ATHN) is a nonprofit network of over 140 federally funded Hemophilia Treatment Centers (HTCs) which provides the infrastructure for clinical and surveillance-based research. ATHN maintains the ATHNdataset (ADS), a "limited dataset" free of protected health information, with data collected on patients with bleeding and clotting disorders at participating HTCs within the Human Resources and Services Administration (HRSA)-supported regional hemophilia networks across the US. The authors acknowledge ATHN, the ATHN-affiliated U. S. Hemophilia Treatment Centers and their 39,000+ patients who have contributed their demographic, clinical, and genetic information to the ATHNdataset. Methods: The objective of this study was to describe the characteristics of pediatric patients diagnosed with VTE in the ADS, focusing on those patients who received a DOAC. Data were abstracted for patients in the ADS who had acute VTE at age <21 years from January 2010 to March 2019. Data extraction included basic demographics and information about VTE and treatment. Results : A total of 1,094 pediatric VTE cases were captured in the ADS. 577 (52.7%) were male. Caucasians were the most prevalent racial group (n = 809; 74%), followed by African-Americans (n = 203; 18.6%).14.9% (n = 163) were Hispanic. Deep venous thrombosis (DVT) was the most prevalent pediatric VTE reported in the ADS (n=889, 81.3%), followed by pulmonary embolism and cerebral venous thrombosis (n=130, 11.9% and n=40, 3.7% respectively). VTE location by age group is listed in Table 1. The most common DVT location was the lower extremities or pelvis, comprising 37.5% (n = 333) of all reported DVTs. Upper extremities or upper thorax DVT occurred less often (n = 211; 23.8 %). 345 (38.8 %) cases were reported only as "DVT" without a specific thrombus location. We reviewed 1,051 anticoagulant prescriptions for 650 VTE patients (mean 1.6 prescriptions per person). Enoxaparin was the most commonly prescribed anticoagulant (n = 676 prescriptions; 64.3%) followed by warfarin (n = 178 prescriptions, 16.9%). Interestingly, 116 (11%) patients, from 21 HTCs, had a DOAC prescribed as their anticoagulant regimen. Anticoagulant prescription by anticoagulant starting age is shown in Table 2. Further analysis of the DOAC subgroup showed that rivaroxaban was the most prescribed DOAC with 77.6% (n = 90/116) of the patients using this agent. Apixaban and dabigatran use was also reported (n= 23, 19.8% and n= 3, 2.6% respectively). The majority of DOACs were prescribed for patients older than 13 years of (111/116, 95.7 %). In children between 3 to 6 years of age (n = 3), rivaroxaban was the only DOAC prescribed. DOACs were primarily used to treat DVT of the extremities (84/116 patients). Other scenarios in which DOACs were also prescribed were PE and abdominal venous thrombosis patients (26, and 4 patients, respectively). Anticoagulant prescription by anticoagulant starting age is shown in Table 2. Conclusion: DVT of the lower extremities and pelvis is the most prevalent pediatric VTE in the ADS. Enoxaparin and warfarin remain the main anticoagulant agents used for pediatric VTE treatment. Despite lack of an FDA-approved pediatric indication, hematologists in US-based HTCs are already using DOACs in pediatric patients with VTE. As further characterization of DOAC use in children is needed, the authors, in collaboration with ATHN, are currently building a multi-institutional retrospective and prospective registry, ATHN 15. This registry will serve as a resource for pediatric hematologists to collect real-world use of DOACs in children, as we await the results of prospective clinical trials. Disclosures Davila: Octapharma: Other: Grant to attend VWD meeting ; Genentech: Other: Advisory board; Spire Learning: Speakers Bureau. Raffini:Bayer: Other: Advisory Board; CSL Behring: Other: Advisory Board; Roche: Other: Advisory Board. Thornburg:Sanofi Genzyme: Research Funding; Bluebird bio: Other: Data Safety Monitoring Board; Genentech: Speakers Bureau; NovoNordisk: Research Funding; Ironwood: Other: Data Safety Monitoring Board; Sanofi Genzyme: Other: Data Safety Monitoring Board. Corrales-Medina:Octapharma: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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