Comparative Analysis of Direct Oral Anticoagulants and Vitamin K Antagonists in Antiphospholipid Syndrome Patients

Introduction Antiphospholipid syndrome (APS) is a major acquired thrombophilia in which vascular thrombosis (venous or arterial) and/or pregnancy losses occur. Despite the use of vitamin K antagonists (VKAs), the annual risk for recurrent thrombosis among APS patients ranges between 2-5% (Crowther et al. NEJM 2003). The evidence for direct oral anticoagulants (DOAC) use in APS patients is still lacking. Therefore, we conducted a retrospective cohort study to explore the efficacy and safety of DOACs vs. VKAs in this patient population. Methods The electronic medical records at Emory University Hospitals were queried for patients ≥18 years old with APS diagnosis, according to the Sydney international census criteria (Miyakis et al. JTH 2006). Included patients must have experienced acute thrombosis between 01/01/2012 and 12/31/2018 and started anticoagulation therapy with DOACs or VKAs. We reviewed patient charts from the index thrombosis date till the end of the study period (12/31/2019). Clinical endpoints were: recurrent vascular thrombosis, clinically relevant bleeding (CRB), which included major and non-major bleeding events as defined by the ISTH society, and composite outcome of thrombosis and bleeding (Kaatz et al. JTH 2015). Patients presenting with pregnancy complications only during the identification period were excluded. Results A total of 153 patients with confirmed APS diagnosis were included in the study. Mean age was 51 (range, 18-79 y.o.). 94 patients (61.4%) were females and 80 patients (52.3%) were white. The most common sites of index thrombosis were pulmonary embolism (N=62, 40.5%), proximal lower extremity deep venous thrombosis (N=49, 32%), and stroke/TIA (N=29, 19%). The majority of patients had a single positive antiphospholipid antibody (aPL) (N=83, 54.2%). 35 (22.9%) had double positive and 24 (15.7%) had triple positive disease. Following index thrombosis, 75 patients started DOAC, whereas 72 started warfarin. Six patients started subcutaneous heparin for a short duration before starting an oral form of anticoagulation. Of those on DOAC, 50 started rivaroxaban while 22 started apixaban. After a mean of 19.8 months (range, 0.68 - 69.8) from the index thrombosis, 62 patients (40.5%) switched to a different class of anticoagulation. The most common reasons for switching therapy were recurrent thrombosis (N=16, 25.8%), followed by patient preference (N=13, 20.9%), side effects including bleeding (N=9, 14.5%), and other reasons, such as confirmed APS diagnosis or renal insufficiency (N=12, 19.3%). We found no statistically significant differences in risk of recurrent thrombosis or CRB events among patients who were started on DOAC vs. VKAs (Figure). The number of arterial thrombosis events was minimal and similar in both treatment groups: N=3 in DOAC group vs. N=5 in the VKA group. Patients treated with rivaroxaban had a similar risk of recurrent thrombosis (log rank, p-value=0.629) and CRB events (log rank, p-value=0.631) compared to those treated with apixaban. The risk of recurrent thrombosis was not affected by degree of aPL positivity or previous history of arterial thrombosis in multivariate models (HR 0.791, 95% CI 0.357 - 1.751) (Table). Discussion and Conclusion Our experience suggests that DOACs -particularly rivaroxaban / apixaban- could be an effective and safe alternative to warfarin in APS patients. We realize that patients with triple aPL positivity constitute a special population with a substantial risk of arterial and venous thrombosis. Given the retrospective nature of our data and that triple aPL positive patients compromised only 15% of our patient population, we conclude that the use of DOACs in these high risk patients remains uncertain. Prospective and large-scale multicenter studies are highly encouraged to explore DOAC use in APS patients with various background profiles. We build on our current experience by starting a multicenter collaboration that will facilitate meaningful subgroup comparisons in APS patients. Figure 1 Figure 1. Disclosures Gaddh: Agios: Consultancy, Other: Advisory board.

High Incidence of Bleeding Found with Direct Oral Anticoagulant Use in Myeloproliferative Neoplasm Patients

BACKGROUND: Patients with myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are at increased risk of arterial (ATE) and venous thromboembolism (VTE). There are no clear guidelines regarding selection of anticoagulation (AC) in MPN patients. Direct oral anticoagulants (DOACs) are increasingly used in the general population to treat a variety of conditions including VTE, ATE, and atrial fibrillation (AF). Data on the safety and efficacy of DOACs in MPNs limited. We conducted a multi-center, retrospective analysis of DOAC use in MPN patients to characterize real-world practice patterns and evaluate thrombosis and bleeding risks. METHODS: We retrospectively analyzed 133 MPN patients prescribed DOACs across the Massachusetts General Brigham / Dana Farber Harvard Cancer Center system from 1995 to 2020. Patients were identified using ICD-9 and 10 codes in the electronic medical record. Patient and treatment characteristics were described with summary statistics. We calculated cumulative incidence functions of VTE and ATE, and major and clinically relevant non-major bleeding (CRNMB) by ISTH criteria, using death on DOAC as a competing risk. A Gray's test was used to compare cumulative incidence between groups. Analysis of risk factors associated with bleeding/thrombosis was carried out by univariate and multivariable Fine-Gray models. RESULTS: Baseline characteristics are displayed in Table 1. Seventy-five (56.4%) MPN patients were prescribed DOAC for VTE, 46 (34.6%) for AF, 7 (5.3%) for stroke, and 5 for other ATE (3.8%). The median age at DOAC initiation was 71; the AF population was significantly older than patients with VTE (75 vs 59, p<0.001). Fifty-seven percent of patients (N = 76) had a diagnosis of PV, with 89% (N = 118) of patients carrying a JAK2 driver mutation. Apixaban was the most commonly prescribed DOAC (N = 83, 62.4%). Nearly half (N = 59, 45%) of patients had a prior VTE/ATE at DOAC initiation, and 23% (N = 31) of patients were switched from warfarin. Among the VTE-treated patients, 43% of events were deep vein thrombosis (N = 39), 31% (N = 28) were pulmonary embolism, 21% (N = 19) were splanchnic vein thrombosis (SVT), and 4.4% (N=4) were other VTE. Table 2 displays practice patterns of DOAC use in MPN patients. The median duration of AC was 37.0 months for all patients, with no difference (p=0.01) between patients treated for AF (42.3 months) and VTE (37.0 months). Twenty-one percent of VTE-treated patients completed a finite course of AC of 6 months median duration. Fifteen percent (N = 11) of VTE-treated and 4.3% (N = 2) of AF patients had reduction to prophylactic dosing. Fifty percent (N = 66) of patients took aspirin and AC concurrently; 83% (N = 110) of patients took cytoreduction with AC. After a median follow-up of 37 months, we found 12 thrombotic (7 arterial, 3 venous, 2 TIPS occlusions) and 28 bleeding (6 major with 4 contributing to patient death, 2 CRNMB) events on DOAC. The estimated 1-year cumulative incidence of thrombosis and bleeding on DOAC was 5.5% (1.5%-9.5%) and 12.3% (6.4%-18.2%), respectively (Figure 1). Thrombosis and bleeding rates were not significantly different between patients treated for VTE versus AF. Prior history of thrombosis and use of dabigatran or edoxaban were significantly associated with increased thrombosis on both univariate and multivariable analysis (p<0.05). Age ≤ 65 also emerged as a risk factor for recurrent thrombosis in multivariate analysis (p=0.04). Use of dabigatran or edoxaban trended toward increased bleeding, but otherwise we found no significant risk factors for bleeding at α=0.05 level, including concomitant aspirin use. DISCUSSION: DOACs are increasingly prescribed in MPN patients for a wide range of indications, with heterogeneity in practice patterns. In our cohort, 1-year thrombosis and bleeding incidence rates on DOAC were 5.5% and 12.3%, respectively. While our 5.5% thrombosis rate is similar to recurrent thrombosis rates reported in MPN patients on DOACs and VKA, our 12.3% bleeding rate appears much higher. This may be related to the complexity of patients seen at our tertiary referral center. The higher-than-expected bleeding rate found in our study indicates the continued need for rigorous evaluation of DOACs in this population, with the gold standard being randomized controlled trials comparing DOAC with warfarin. Figure 1 Figure 1. Disclosures Neuberg: Madrigal Pharmaceuticals: Other: Stock ownership; Pharmacyclics: Research Funding. Rosovsky: Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Inari: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hobbs: Bayer: Research Funding; Merck: Research Funding; AbbVie.: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Incyte Corporation: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding. Connors: Abbott: Consultancy; Bristol-Myers Squibb: Honoraria; takeda: Honoraria; Alnylam: Consultancy; Pfizer: Honoraria; CSL Behring: Research Funding.

Results of the International Survey on Adherence with Anticoagulation in Children, Adolescents and Young Adults

Introduction Children, adolescents, and young adults are prescribed chronic anticoagulation with oral and parenteral medications for treatment and prevention of thrombosis. Non-adherence to the recommended dosing, schedule, and monitoring of anticoagulants may lead to poor treatment outcomes. Considering that little is known about adherence to anticoagulation in children, this survey aimed to evaluate provider practices and experiences related to pediatric, adolescent, and young adult patient adherence with anticoagulation. Methods A REDCap ® survey was developed by members of the International Haemostasis and Thrombosis Pediatric and Neonatal Scientific Subcommittee Medication Adherence Working Group. Questions regarding current clinical practices related to medication adherence (i.e., assessment, barriers to addressing adherence) were developed by the multi-disciplinary working group with expertise in anticoagulation, medication adherence, and hematology research. The survey was distributed in electronic form to more than 500 clinicians through the International Society of Haemostasis and Thrombosis plus related professional organizations in the United States, Switzerland, New Zealand, and Australia. Clinicians are eligible for the study if they are involved in anticoagulation management in children and/or adolescents and young adults. Results A total of 112 clinicians completed surveys. The majority (n = 104 , 93%) were pediatric hematology/oncology physicians. Demographic and clinical practice characteristics are shown in Table 1. Ninety-nine (88%) respondents reported that medication adherence is typically assessed for patients in their practice prescribed anticoagulation. Details regarding medication adherence clinical practices are shown in Table 2. Forty-eight (43%) reported that they often or always worry about medication adherence in patients prescribed anticoagulation. While most clinicians (n = 83, 74%) reported they are often or always confident in addressing non-adherence, only 30% (n = 34) reported that they are often or always confident about identifying patients who are non-adherent and only 50 (45%) reported that they often or always have the resources to effectively address non-adherence. Fifty-five (49%) respondents indicated that they had cases where non-adherence resulted in new or recurrent thrombosis and 20 (18%) indicated that they had cases where non-adherence resulted in bleeding. In response to the free text question: "What types of resources would make it easier to measure adherence in your clinic?," themes emerged regarding tools (i.e., validated instruments and electronic apps to measure adherence), communication with pharmacy, and more time and staffing in clinic. When asked: "When you identify a patient/family who is struggling to take their anticoagulation as prescribed or follow-up with labs or appointments for anticoagulation, what do you do?," clinicians discussed identification of barriers; education; involving additional staff including nursing, social work, and pharmacy; consider switching anticoagulation; increase frequency of calls, clinic visits and/or labs; and use of reminders. Some providers reported utilizing shared decision-making or motivational interviewing to improve adherence. Conclusions Clinicians who prescribe anticoagulation for children, teens, and young adults identify medication non-adherence as a clinically significant issue that may result in recurrent thrombosis or bleeding. Clinicians perceive that non-adherence most often occurs when patients skip doses and/or do not follow monitoring recommendations. Current gaps in clinical practice include resources to identify patients who are non-adherent and strategies to improve adherence. A multi-disciplinary team including nurses, physicians, pharmacists, social workers, and psychologists who have dedicated time for anticoagulation management could potentially improve outcomes for children prescribed anticoagulation. As direct oral anticoagulants are approved for children and adolescents, the impact on medication adherence with these treatment options should be evaluated. Figure 1 Figure 1. Disclosures Thornburg: HemaBiologics: Honoraria; CSL Behring: Honoraria; Octapharma: Honoraria; Biomarin: Honoraria, Research Funding; Genentech: Honoraria; Bluebird Bio: Other: data safety monitoring board; Ironwood Pharmaceuticals: Other: data safety monitoring board.

Apixaban compared with warfarin to prevent thrombosis in thrombotic antiphospholipid syndrome: a randomized trial

Thrombotic antiphospholipid syndrome (TAPS) is characterized by venous, arterial, or microvascular thrombosis. Patients with TAPS merit indefinite anticoagulation and warfarin has historically been the standard treatment. Apixaban is an oral factor Xa inhibitor anticoagulant that requires no dose adjustment or monitoring. The efficacy and safety of apixaban compared with warfarin for TAPS patients remain unknown. This multicenter prospective randomized open-label blinded endpoint study assigned anticoagulated TAPS patients to apixaban or warfarin (target INR 2-3) for 12 months. The primary efficacy outcome was clinically overt thrombosis and vascular death. Apixaban was first given at 2.5 mg twice daily. Two protocol changes were instituted based on recommendations from the data safety monitoring board. After the 25th patient was randomized, the apixaban dose was increased to 5mg twice daily, and after the 30th patient was randomized, subjects with prior arterial thrombosis were excluded. Primary outcomes were adjudicated by independent experts blinded to treatment allocation. Patients randomized between 23 February 2015 and 7 March 2019 to apixaban (n=23) or warfarin (n=25) were similar. Among the components of the primary efficacy outcome, only stroke occurred in 6 of 23 patients randomized to apixaban compared with 0 of 25 patients randomized to warfarin. The study ended prematurely after the 48th patient was enrolled. Conclusions from our study are limited due to protocol modifications and low patient accrual. Despite these limitations, our results suggest that apixaban may not be routinely substituted for warfarin to prevent recurrent thrombosis (and especially stokes) among patients with TAPS (ClinicalTrials.gov: NCT02295475).

Management of Phlegmasia Cerulea Dolens Caused by a Giant Leiomyoma

This case is of a young female with a large uterine leiomyoma causing phlegmasia cerulea dolens with thrombosis of the left common and left external iliac veins. She underwent mechanical thrombectomy to temporize the condition until she could be evaluated by gynecology-oncologist to remove the cause of venous obstruction. Prior to hysterectomy, suprarenal inferior vena cava filter was placed. Less than 12 hours post hysterectomy she developed recurrent thrombosis involving the left common and external iliac veins. She underwent repeat mechanical thrombectomy with wall stent placement in the left common iliac vein with resolution of her symptoms.

Antiphospholipid antibodies and their clinical significance

Обзор посвящён антифосфолипидным антителам (аФЛ) и их клинико-диагностической ценности. Рассматриваются вопросы стандартизации методов исследования аФЛ, в частности твердофазных тест-систем, одним из представителей которых является хемилюминесцентый анализ. Обсуждаются патогенетические аспекты антифосфолипидного синдрома (АФС) и описываются пути влияния аФЛ на различные компоненты гемостаза. Дается подробная характеристика β2-гликопротеина 1 (β2-ГП1) с описанием доменов. Подробно изучены клинические проявления и взаимосвязь «экстра»-критериальных аФЛ: IgA антител к кардиолипину (IgA-аКЛ), IgA антител к β2-ГП1 (IgA-аβ2-ГП1), антител к домену I β2-ГП1 (аβ2-ГП1-DI), антител к комплексу фосфатидилсерин–протромбин и аФЛ, не входящих в Сиднейские диагностические критерии АФС. Antiphospholipid syndrome (APS) is an acquired autoimmune thrombophilia in which patients have clinical signs of recurrent thrombosis and morbidity during pregnancy and constantly test positive for antibodies against phospholipid (aPL). At least one clinical (vascular thrombosis or pregnancy) and one laboratory (positive test result for anticoagulant lupus, anticardiolipin antibodies and/or anti-β2-glycoprotein 1 antibodies) must be performed in order for the patient to be classified as having APS. However, the clinical and laboratory APS spectra cover additional manifestations. Research interest is increasingly focused on developing new assays that may be more specifi c to APS than current aPL tests. This review focuses on extra criterion antiphospholipid antibodies — IgA antibodies to cardiolipin (IgA-aCL), IgA antibodies to β2-glycoprotein 1 (IgA-aβ2-GP1), antibodies to phosphatidylserine-prothrombin complex. A detailed description of aβ2-GP1 with a description of domains is given. The questions of standardization of aPL research methods, in particular, solid-phase test systems, one of which is chemiluminescent analysis, are examined.