Warfarin Anticoagulation Research Articles

Abstract 11608: DOAC Effect on Cardiovascular Outcomes in Patients with Peripheral Arterial Disease

Introduction: Peripheral arterial disease (PAD) increases cardiovascular (CV) morbidity and mortality, but remains underdiagnosed and undertreated. Several trials support low-dose rivaroxaban in PAD treatment, although this has yet to be widely adopted in clinical practice. The effect of warfarin and direct oral anticoagulants (DOACs) on comprehensive PAD outcomes warrants further study. Hypothesis: Anticoagulant therapy, particularly DOACs, improves CV outcomes in PAD. Methods: We conducted a retrospective study of patients who underwent ankle-brachial index testing (ABI) from 1996 – 2020 at Mayo Clinic. We included patients with PAD defined by abnormal ABI (<1.0 or >/=1.4). Prolonged (>6 months) DOAC or warfarin use was compared to no anticoagulant therapy. Multivariable (MV) regression, controlling for baseline CV risk factors, was used. Results: 21,891 patients had abnormal ABI readings; 3,093 were on warfarin and 267 were on DOAC for any indication. Anticoagulation improved mortality, with DOACs superior to warfarin. DOACs improved critical limb ischemia (CLI)/amputation in univariate analysis, although this was not significant in MV. Patients with poorly compressible vessels (ABI >/=1.4) had increased limb outcomes compared to reduced ABI (<1.0). Ischemic stroke and myocardial infarction occurred more frequently in those on anticoagulation, but the risk was less for DOACs vs. warfarin. Notably, both anticoagulant groups had greater baseline comorbidity than the non-anticoagulant group; the DOAC and warfarin groups were similar. Major bleeding (6.7%) was increased in both anticoagulant groups, but less so with DOACs and this was similar to the bleeding risk seen with aspirin (HR 1.20). Conclusion: Anticoagulant therapy improved mortality in a large cohort of PAD patients. The risk of limb events appears improved in those on DOACs. DOACs showed improved risk profiles compared to warfarin regarding CV and bleeding outcomes.

Abstract 13708: Left Ventricular Thrombus in Patients With Takotsubo Cardiomyopathy in the US Veteran Affairs Healthcare System

Introduction: Takotsubo cardiomyopathy is characterized by significant transient left ventricular (LV) dysfunction that is not due to obstructive coronary artery disease. LV thrombus is a known complication of Takotsubo cardiomyopathy, but the outcomes of these patients are not well described in the literature. The aim of our study was to investigate the rates and outcomes of patients diagnosed with Takotsubo cardiomyopathy with LV thrombus in the Veteran Affairs (VA) system. Methods: We performed a retrospective study using chart review for patients diagnosed with Takotsubo cardiomyopathy between 2005 and 2018 in the VA national database. We included patients who met the Mayo Clinic diagnostic criteria for Takotsubo cardiomyopathy. We collected data for demographics, clinical course, and outcomes. Results: 320 patients (69% males) were included. Median age was 64 years, 20.3% were known to have coronary artery disease, 34.7% had Diabetes and 61.3% had hypertension. 96.8% of patients had Apical variant of Takotsubo cardiomyopathy. LV thrombus was diagnosed in 8.8% of patients, all of those patients had apical variant of Takotsubo cardiomyopathy. There were no significant differences in the mortality rates in the hospital (14.3% vs 7.4%, p=0.15) and at 30-day follow up (4.2% vs 1.9%, p=0.45) in patients who developed LV thrombus compared to patients who did not. For patients who developed LV thrombus, only 1 patient developed a stroke on 30-day follow up; that patient was on therapeutic doses of warfarin for anticoagulation at the time of the stroke. Conclusions: In patients diagnosed with Takotsubo cardiomyopathy with LV thrombus, there was no significant difference in mortality rates in the hospital or at 30 day follow up when compared to patients with no LV thrombus. Only one of those patients developed a stroke during follow up, suggesting that the embolic risk is low with appropriate treatment.

Abstract 11915: Less Aspirin, Less Bleeding for Patients on Chronic Warfarin Anticoagulation for Atrial Fibrillation and/or Venous Thromboembolic Disease

Introduction: For some patients on chronic warfarin anticoagulation for atrial fibrillation and/or venous thromboembolic disease, the addition of aspirin (ASA) may increase bleeding with uncertain therapeutic benefit. Between 2017 and 2018, the six-center Michigan Anticoagulation Quality Improvement Initiative implemented a multi-center quality improvement project to reduce excess aspirin use. Hypothesis: We anticipated reductions in overall ASA use and bleeding. Methods: Warfarin treated patients taking ASA without a clear indication (eg. coronary artery disease) were identified. Their primary care provider was contacted to advise if ongoing ASA+warfarin was recommended. ASA was discontinued if suggested by their doctor. Data was abstracted by trained abstractors using predefined forms. In December 2019, we evaluated monthly rates of excess ASA use, bleeding, and thrombotic outcomes. Data were analyzed using piecewise linear regression. Results: We followed 6,738 patients for a median (interquartile range) of 6.7 months (3.2-19.3 months). Aspirin use declined significantly over the 24 months before our intervention (P<0.001) with an accelerated decline post intervention (p=0.001, Figure 1). Our intervention was associated with a non-significant decline in bleeding (p=0.12), emergency room (ER) visits for bleeding (p=0.35), admissions for bleeding (p=0.97), a significant decline in major bleeding (p=0.029), and no significant change in thrombotic outcomes (p=0.34). Including the decline in ASA use starting 24 months pre-intervention, reducing ASA use resulted in significant declines in any bleeding, major bleeding, and ER visits for bleeding (p=0.021, p=0.001, p=0.038 respectively). There remained no change in thrombotic outcomes (p=0.36). Conclusions: Our quality improvement intervention reduced aspirin use. Reductions in aspirin use were associated with reduced bleeding outcomes without increased thrombotic outcomes.

Abstract 14132: The Crystal Structures Of Human Cytochrome P450 2C9 Provide Insights Into The Effect Of Genetic Variation And The Binding Of Losartan

The human cytochrome P450 2C9 (CYP2C9) enzyme metabolizes many of the currently available medications that include anti-coagulant warfarin, anti-hypertensive losartan, anti-diabetics tolbutamide and glimepiride. Genetic variations in CYP2C9 that include the common alleles *2 and *3 have resulted in reduced enzyme activity leading to altered metabolism of various drug substrates compared with the wild-type (WT). The CYP2C9*2 genetic variant represent an amino acid change from arginine to cysteine at position 144. The crystal structure of CYP2C9 WT and the *2 variant complexed with losartan were recently published. However, the structure of these enzymes in the absence of any ligand or losartan is not available. Thus, the aim was to determine the ligand free structure of these enzymes and assess the hypothesis that the drug binding orchestrates the conformational change and leads to reorientation of amino acid sidechains to interact with losartan in the active site. The data for the CYP2C9 WT and the CYP2C9*2 crystals in the absence of any ligands was collected remotely at the Stanford Synchrotron Radiation Light Source and the structures were solved using x-ray crystallography. The ligand-free structure of the *2 variant revealed markedly different conformation compared to the recently published structure in complex with losartan. The changes in the F, F’, G and G’ helices indicate an open conformation in the absence of losartan compared to the losartan complex. Whereas the ligand-free structure of the WT illustrated similarity in the overall conformation to the previously published structures with losartan bound. Comparison of the ligand free structure of the CYP2C9 WT or the *2 variant with the losartan bound structure identified the amino acid sidechains important for interaction with the drug in the active site. Furthermore, the structure of the *2 variant in the absence or presence of losartan provided a useful framework to investigate the effect of amino acid substitution that leads to altered binding of the drug. In conclusion, the structural characterization of the CYP2C9 WT and the *2 variant yield insights into the conformational changes that occur upon binding of losartan and help understand the effect of genetic polymorphisms on drug metabolism.

Association of Race and Ethnicity and Anticoagulation in Patients With Atrial Fibrillation Dually Enrolled in Veterans Health Administration and Medicare: Effects of Medicare Part D on Prescribing Disparities.

Racial and ethnic disparities in anticoagulation exist in atrial fibrillation management in Medicare and the Veterans Health Administration, but the influence of dual Veterans Health Administration and Medicare enrollment is unclear. We compared anticoagulant initiation by race and ethnicity in dually enrolled patients and assessed the role of Medicare part D enrollment on anticoagulation disparities. We identified patients with incident atrial fibrillation (2014-2018) dually enrolled in Veterans Health Administration and Medicare. We assessed any anticoagulant initiation (warfarin or direct-acting oral anticoagulants [DOACs]) within 90 days of atrial fibrillation diagnosis and DOAC use among anticoagulant initiators. We modeled anticoagulant initiation, adjusting for patient, provider, and facility factors, including main effects for race and ethnicity and Medicare part D enrollment and an interaction term for these variables. In 43 789 patients, 8.9% were Black, 3.6% Hispanic, and 87.5% White; 10.9% participated in Medicare part D. Overall, 29 680 (67.8%) patients initiated any anticoagulant, of whom 17 568 (59.2%) initiated DOACs. Lower proportions of Black (65.2%) than Hispanic (67.6%) or White (68.0%) patients initiated any anticoagulant (P=0.001) and, lower proportions of Black (56.3%) and Hispanic (55.9%) than White (59.6%) patients (P=0.001) initiated DOACs. Compared with White patients, Black patients had significantly lower initiation of any anticoagulant (adjusted odds ratio, 0.89 [95% CI, 0.82-0.97]). The adjusted odds ratios for DOAC initiation were significantly lower for Black (0.72 [95% CI, 0.65-0.81]) and Hispanic (0.84 [95% CI, 0.70-1.00]) than White patients. The interaction between race and ethnicity and Medicare part D enrollment was nonsignificant for any anticoagulant (P=0.99) and DOAC (P=0.27) therapies. In dually enrolled Veterans Health Administration and Medicare patients with atrial fibrillation, Black patients were less likely to initiate any anticoagulant, and Black and Hispanic patients were less likely to initiate DOACs. Medicare part D enrollment did not moderate the associations between race and ethnicity and anticoagulant therapies.

Transitioning Eligible Patients from Warfarin to a Direct Oral Anticoagulant: A Prospective Quality Improvement Study

Background:Direct oral anticoagulants (DOACs) are rapidly replacing alternative agents as the preferred choice for anticoagulation. With extended time on the market and expanded guidelines for indications for use, they are now more accessible and affordable. Qualifying patients previously treated with warfarin for long-term anticoagulation may benefit from transitioning to a DOAC. In this prospective quality improvement study, we seek to identify eligible patients and transition them from warfarin to DOAC via shared decision-making and a multidisciplinary approach. Additionally, we will assess changes in quality of life (QOL) through a validated survey.Methods:Identify patients currently on warfarin who are eligible for transition to a DOAC. Eligibility criteria include patients with age >18 years old. Exclusion criteria includes pregnancy, BMI >50 kg/m2, CrCl <15 L/min, patients receiving anticoagulation for APLS or for mechanical heart valves. With the aid of our pharmacy team, we then ensure long-term medication affordability prior to transition. Eligible patients complete a QOL survey pre-transition and 3 months post-transition. The QOL survey is the validated Anti-Clot Treatment Scale (ACTS), which is a 15 question survey which includes a Burden scale composed of 12 questions and a Benefit scale composed of 3 questions and each question is scored from 1 to 5 (1=not at all, 2=a little, 3=moderately, 4=quite a bit, 5=extremely). The Burden scale is reverse scored so that higher ACTS Burden scores indicate greater satisfaction for a score range of 12-60. The Benefit scale is scored conventionally for a score range of 3-15. The Total score is calculated by the addition of the Burden scale and Benefit scale for a score range of 15-75. Paired T-tests were conducted on the Burden scale, Benefit scale, and Total score using GraphPad Prism version 7 (GraphPad Software, La Jolla, CA). P-values were two-tailed, with a p<0.05 considered statistically significant.Results:25 patients out of 60 were identified as eligible for DOAC transition. Total score, Burden scale, and Benefit scale mean values were 49.5, 39.5, 10 for warfarin and 66.8, 53.5, and 13.3 for DOAC, respectively. Preliminary conducted analysis revealed statistically significant improvements in Total, Burden, and Benefit scores with p-values of 0.0046, 0.0075, and 0.0319 and mean improvements of 17.3, 14, and 3.25, respectively.Conclusion:Transitioning patients from warfarin to a DOAC has been found to decrease both patients' sense of burden while also improving their sense of benefit, as evidenced by the QOL survey analysis. Transitioning patients from warfarin to a DOAC has the potential to decrease need for routine INR monitoring, dietary limitations, and fewer drug interactions. Additionally, it improves patient satisfaction with their healthcare and reduces utilization of healthcare resources. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Efficiency of the Left Atrial Appendage Thrombus Dissolution in Patients with Persistent Nonvalvular Atrial Fibrillation with Warfarin or Direct Oral Anticoagulants Therapy

Aim. Compare the incidence of the left atrial appendage (LAA) thrombus dissolution in patients with persistent nonvalvular atrial fibrillation receiving warfarin and direct oral anticoagulants (DOAC).Materials and methods. 68 patients with persistent nonvalvular atrial fibrillation were included in a retrospective study (age was 59.7±9.8 years, 60.3% men), in whom at least one repeated transesophageal echocardiographic examination was performed after detecting a thrombus. After detecting a thrombus in the LAA, 37 (54.4%) patients started or continued taking warfarin in doses that ensure the INR maintenance at the level of 2-3, 14 (20.6%) started or continued taking dabigatran at a dose of 150 mg 2 times/day, 14 (20.6%) started or continued taking rivaroxaban 20 mg 1 time/day and 3 (4.4%) started or continued taking apixaban 5 mg 2 times/day. Repeated transesophageal echocardiographic examination was performed on average 33.3±14.2 days after the first one.Results. Dissolution of a previously identified thrombus was found in 26 (83.9%) of 31 patients receiving DOAC and in 19 (51.4%) of 37 patients receiving warfarin (p=0.011). The logistic regression analysis showed that the chances of a thrombus dissolution in LAA while taking DOAC are 14.8 times (95% confidence interval [CI] was 2.469-88.72) higher than while taking warfarin. The size and the rate at which blood is expelled from the LAA also have an independent influence on the chances of thrombus dissolution. An increase in the size of a thrombus by 1 mm reduces the chances of a thrombus dissolution by 1.136 (95% CI was 1.040-1.244) times, and an increase in the rate of blood expulsion from the LAA by 1 cm/sec increases these chances by 1.105 (95% CI was 1.003-1.219) times.Conclusion. In the present study, the incidence of the LAA thrombus dissolution in patients with persistent nonvalvular atrial fibrillation while receiving DOAC was higher than while receiving warfarin.

Direct Oral Anticoagulants for Stroke Prevention in Patients with Atrial Fibrillation and Bioprosthetic Heart Valves

Direct Oral Anticoagulants for Stroke Prevention in Patients with Atrial Fibrillation and Bioprosthetic Heart Valves

EVALUATION OF APPROPRIATE USE OF PEDIATRIC FRESH FROZEN PLASMA IN A TERTIARY CARE HOSPITAL

Fresh frozen plasma (FFP) is the primary source of coagulation factors. Indications of FFP use are very limited such as disseminated intravascular coagulation, massive bleeding, thrombotic thrombocytopenic purpura, biopsy for chronic liver disease, and reversing warfarin anticoagulation with severe bleeding. In clinical practice, FFPs are reported to be used inappropriately either in respect of the particular indication or excessive in adult studies. Therefore, we aimed in this study to evaluate indications of pediatric FFP usage in our tertiary care hospital Patients aged 0-18 years, who were hospitalized in Ankara City Hospital Children's Hospital between September and December 2020, were analyzed retrospectively. Demographic information, diagnosis, FFP transfusion indication, pre-transfusion coagulation results, surgical procedure and bleeding status, and the amount of FFP administered were recorded. Statistical analysis was done with SPSS 18.0 program. 1110 units of FFP were transfused to 324 patients (57% males) in 987 transfusion episodes. The mean age of the patients was 5.4±5.7 years68% of the transfusion episodes had a pre-transfusion coagulation testing. 249 (25%) of the transfusion episodes were given before or after minor or major surgery, and 226 (23%) were for plasmapheresis. The most FFP usage was in pediatric and cardiovascular surgery intensive care and hematology/oncology clinics. 69% of the FFP transfusions were appropriate. Misuse of FFP exposes patients to unpredictable adverse effects such as allergic reactions, infectious complications, hemolysis, fluid overload, and transfusion-induced acute lung injury (TRALI). In this study, the use of FFP in children was evaluated for the first time in our country, and it was found that the 31% of the FFP transfusions was inappropriate. Regular audit and education programs for the efficient use of FFP by hospital transfusion committees can improve transfusion practices.

Precise Warfarin Management through Personalized Modeling and Control with Limited Clinical Data.

Warfarin belongs to a medication class called anticoagulants or blood thinners. It is used for the treatment to prevent blood clots from forming or growing larger. Patients with venous thrombosis, pulmonary embolism, or who have suffered a heart attack, have an irregular heartbeat, or prosthetic heart valves are prescribed with warfarin. It is challenging to find optimal doses due to inter-patient and intra-patient variabilities and narrow therapeutic index. This work presents an individualized warfarin dosing method by utilizing the individual patient model generated using limited clinical data of the patients with chronic conditions under warfarin anticoagulation treatment. Then, the individual precise warfarin dosing is formalized as an optimal control problem, which is solved using the DORBF control approach. The efficiency of the proposed approach is compared with results obtained from practiced clinical protocol.

Safety of direct oral anticoagulants in solid organ transplant recipients: A meta-analysis.

There is limited evidence comparing direct oral anticoagulants (DOACs) and warfarin in solid organ transplant (SOT) recipients. We performed a pooled analysis to study the safety and efficacy of DOACs in this patient population. We searched PubMed, Embase, and Scopus databases using the search terms "heart transplant" or "lung transplant" or "liver transplant" or "kidney transplant" or "pancreas transplant" and "direct oral anticoagulant" for literature search. Random effects model with Mantel-Haenszel method was used to pool the outcomes. Pooled analysis included 489 patients, of which 259 patients received DOACs and 230 patients received warfarin. When compared to warfarin, the use of DOACs was associated with decreased risk of composite bleed (RR .49, 95% CI .32-.76, p=.002). There were no differences in rates of major bleeding (RR .55, 95% CI .20-1.49, p=.24) or venous thromboembolism (RR .65, 95% CI .25-1.70, p=.38) between the two groups. Evidence from pooled analysis suggests that DOACs are comparable to warfarin in terms of safety in SOT recipients. Further research is warranted to conclusively determine whether DOACs are safe alternatives to warfarin for anticoagulation in SOT recipients.

O16 A diagnosis of BehÇet’s Disease with secondary antiphospholipid syndrome

O16 A diagnosis of BehÇet’s Disease with secondary antiphospholipid syndrome

O21 A case of thromboembolic ischaemic cardiomyopathy and intracardiac thrombus in a patient with antiphospholipid syndrome

Abstract Case report - Introduction Commonly found in association with lupus, antiphospholipid syndrome (APLS) is a potentially life-threatening disease of which an understanding is essential for rheumatologists. In addition to well-recognised sequelae such as pulmonary embolism and obstetric complications, APLS can provoke thrombi ranging from microscopic to massive in size in a wide range of arterial and venous territories. We present the case of a young woman with APLS who suffered significant morbidity as a result of intracardiac and coronary thromboembolism shortly after becoming pregnant and switching anticoagulant therapy, highlighting the importance of vigilance and investigation for rarer thromboses in APLS patients. Case report - Case description A 34-year-old woman with known APLS and 5 weeks pregnant was admitted to hospital with a history of headache, nausea/vomiting and mild photophobia followed by fever, shortness of breath, confusion, pleuritic chest pain and lower limb swelling. She had commenced enoxaparin in place of warfarin on becoming pregnant. Examination was suggestive of cardiac failure. Troponin and NTproBNP were markedly elevated, without ischaemic ECG changes. A brain CT venogram was reported as normal, but echocardiogram revealed a dilated LV with reduced ejection fraction (39%), inferior and lateral wall hypokinesia and possible LV thrombus. She was treated initially for myocarditis (presumed viral or autoimmune) and received antibiotics given her raised WCC and CRP. Treatment dose enoxaparin was continued. Bloods revealed anaemia, thrombocytopenia, and positive immunology: cardiolipin IgG 123U/ml, IgM 612, anti-B2GP1 IgG 19/IgM 607, ANA (1/320) and RNP 70. C3 was normal (0.8) and C4 low (0.03). A livedoid rash consistent with APLS was present on the trunk, but there were no other clinical manifestations of connective tissue disease. Repeat CT venogram performed after the patient reported worsening headaches revealed a small tentorial subdural haematoma, resulting in the reversal of enoxaparin with protamine. Later review of these images suggested a stable 5mm haematoma that was present on the earlier scan, and enoxaparin was recommenced. Cardiac MRI revealed extensive infarct with contained LV wall rupture. Coronary angiography showed normal vessels. LVEF on repeat echocardiogram fell to 28%. Surgical pregnancy termination was performed in accordance with patient wishes, with subsequent reversion to warfarin anticoagulation. Repeat MRI showed thinned anterior/lateral LV walls, evidence of transmural myocardial fibrosis and residual laminar thrombus, and bubble echo demonstrated no PFO. The patient was ultimately managed for presumed microembolic myocardial infarction with resulting heart failure, and has been referred to a cardiac transplant centre. Case report - Discussion This case highlights the potential risk associated with a relatively common scenario: anticoagulant switching in females with APLS at the start (or in anticipation) of pregnancy. In this case our patient started enoxaparin 80mg BD 48 hours after discontinuing warfarin, developing symptoms consistent with intracerebral thrombosis shortly afterwards, followed by those of heart failure. The possible diagnoses on the basis of the patient’s initial presentation were numerous, and she was appropriately investigated in the first instance for a possible cerebral thrombotic event with cranial CT and venogram. On development of cardiorespiratory symptoms, there was a delay in requesting investigations (troponin, BNP) that may have pointed towards myocardial pathology, and once these investigations were noted to be abnormal the patient was managed as a probable myocarditis in keeping with most other patients of her age without a significant past medical history. Perhaps insufficient diagnostic weight was given to her known thrombophilia and recent medication change, which may have prompted closer review of her brain imaging leading to earlier detection of the subdural haematoma. It may also have led to more rapid investigation for possible thrombus elsewhere via earlier echo, CTPA or cardiac MRI. The latter investigation was ultimately crucial in definitively showing myocardial injury to be the result of infarction rather than inflammation, where prior ECGs had not suggested ischaemia. The subsequent unremarkable coronary angiogram added weight to the likely thromboembolic nature of the infarction, potentially via multiple microemboli being thrown off the LV thrombus. The precise timing of the presumed embolisation to our patient’s coronary circulation is unclear, and the absence of overt ischaemic cardiac symptoms suggests this may have been a relatively prolonged, subacute process. Earlier recognition of the thrombotic nature of this event may have prevented myocardial injury if embolic showers continued into her inpatient stay. Case report - Key learning points

Age-adjusted risk factors are independently associated with an increased risk of major bleeding during the two-year follow-up of the ETNA-AF-Europe registry

Abstract Background Non-vitamin K antagonist oral anticoagulants (NOACs) are a preferred treatment option over warfarin for anticoagulation in patients with atrial fibrillation (AF). Management decisions for thromboprophylaxis in AF need to balance the risk of stroke against the risk of bleeding. Various patient characteristics have been identified as independent risk factors for bleeding. A substantial number of bleeding events might be prevented if independent predictors of bleeding were identified. Purpose The present analysis aims at assessing age-adjusted risk predictors of major bleeding during two-year follow-up of unselected European patients with AF in the ETNA-AF-Europe registry. Methods ETNA-AF-Europe is a prospective, multi-centre, post-authorisation, observational study conducted in 825 centres enrolling patients treated with edoxaban once daily in 10 European countries. Wald Chi square tested the association between risk predictors and major bleeding after adjusting for age, given that age is a well-known, strong predictor of anticoagulation-related bleeding in patients with AF. Results Overall, 13,417 patients with AF (edoxaban 60 mg: n=10,248; edoxaban 30 mg: n=3169) completed the two-year follow-up. The mean age was 73.6±9.5 years, with ∼84% of the patients aged over 65 years. Mean CHA2DS2-VASc and HAS-BLED scores were 3.2 and 2.5, respectively. 438 (3.3%) patients had a history of bleeding events at baseline, of which 138 (1.0%) had a history of major bleeding event. Univariate analysis demonstrated that recalculated glomerular filtration rate (Cockcroft-Gault Equation) (GFR-CG) at baseline was the strongest age-adjusted predictor of major bleeding (Wald Chi-Square: 31.84; p&amp;lt;0.0001) (Figures 1 and 2), followed by history of major or clinically relevant non-major (CRNM) bleeding (24.08; p&amp;lt;0.0001), HAS-BLED score (21.10; p&amp;lt;0.0001), history of heart failure (derived) (16.59; p&amp;lt;0.0001), subjective frailty as assessed by physician (17.35; p=0.0002), history of major bleeding (14.14; p=0.0002), chronic obstructive pulmonary disease (COPD) (12.84; p=0.0003), CHA2DS2-VASc (12.14; p=0.0005), history of myocardial infarction (MI) (7.79; p=0.005), and left ventricular ejection fraction (LVEF) categorised by 40% (5.45; p=0.02). Conclusion Bleeding events on therapy with edoxaban can be predicted by quantifying kidney disease and capturing information on heart failure, frailty, prior bleeding, chronic obstructive lung disease and history of myocardial infarction. These data highlight the need for optimal management of anticoagulation therapy and close follow-up of patients with such risk profiles. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Europe GmbH Figure 1. GFR-CG as a predictor of major bleedingFigure 2. Predictors of major bleeding

Management of patients with hip fracture receiving anticoagulation: What are we doing in Canada?

Background:Direct oral anticoagulants (DOACs) are rapidly replacing warfarin for therapeutic anticoagulation; however, many DOACs are irreversible and may complicate bleeding in emergent situations such as hip fracture. In this setting, there is a lack of clear guidelines for the timing of surgery. The purpose of this study was to evaluate the current practices of Canadian orthopedic surgeons who manage patients with hip fracture receiving anticoagulation.Methods:In January–March 2018, we administered a purpose-specific cross-sectional survey to all currently practising orthopedic surgeons in Canada who had performed hip fracture surgery in 2017. The survey evaluated approaches to decision-making and timing of surgery in patients with hip fracture receiving anticoagulation.Results:A total of 280 surgeons representing a mix of academic and community practice, seniority and fellowship training responded. Nearly one-quarter of respondents (66 [23.4%]) were members of the Canadian Orthopaedic Trauma Society (COTS). Almost three-quarters (206 [73.6%]) felt that adequate clinical guidelines for patients with hip fracture receiving anticoagulation did not exist, and 177 (61.9%) indicated that anesthesiology or internal medicine had a greater influence on the timing of surgery than the attending surgeon. A total of 117/273 respondents (42.9%) indicated that patients taking warfarin should have immediate surgery (with or without reversal), compared to 63/270 (23.3%) for patients taking a DOAC (p < 0.001). Members of COTS were more likely than nonmembers to advocate for immediate surgery in all patients (p < 0.05).Conclusion:There is wide variability in Canada in the management of patients with hip fracture receiving anticoagulation. Improved multidisciplinary communication, prospectively evaluated treatment guidelines and focus on knowledge translation may add clarity to this issue. Level of evidence: IV.

THE PARADOXICAL PRESENTATION OF PRE-ECLAMPSIA WITH DIFFUSE ALVEOLAR HEMORRHAGE AND VENOUS THROMBOSIS AS CLINICAL MANIFESTATIONS OF ANTIPHOSPHOLIPID SYNDROME

TOPIC: Pulmonary Manifestations of Systemic Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Antiphospholipid Syndrome (APS) is an autoimmune disorder clinically defined by the presence of antiphospholipid antibodies (aPL), history of arterial or deep venous thrombosis (DVT), and/or repeat episodes of early pregnancy loss. Due to the increased risk for thrombosis, often overlooked is a rare and seemingly paradoxical association between APS and diffuse alveolar hemorrhage (DAH) - a disorder characterized by non-localized alveolar bleeding. Rare manifestation of APS presenting with preeclampsia, DAH, and DVT offers a variety of multi-disciplinary challenges. CASE PRESENTATION: A 34-year-old G6P3 woman at 28 weeks gestation with a remote history of pulmonary embolism (PE), presented to the Emergency Department with a two-day history of dyspnea and hemoptysis. Exam was remarkable for sinus tachycardia, grade 3 systolic murmur at the apex, and increased work of breathing with bilateral pulmonary rhonchi. Computed tomography (CT) scan demonstrated centrally predominant opacities without signs of PE. Bronchoscopy was significant for diffusely hemorrhagic airways with progressively hemorrhagic serial lavage aliquots. Emergent delivery was performed in the setting of Preeclampsia while high-dose steroids were administered for DAH. The patient returned to baseline over the next 3 days without returning signs of hemoptysis. Lupus anticoagulant was positive but PT and PTT were both normal. Steroids were discontinued and therapeutic enoxaparin was started for a possible novel diagnosis of APS.Six days later, she reexhibited hemoptysis. Repeat CT revealed bilateral alveolar infiltrates consistent with the recurrence of DAH. Disproportionate left lower extremity edema and a femoral vein DVT were also discovered. Anticoagulation was again withheld, high-dose steroids were re-started, and an inferior vena cava filter was placed. Repeat lupus anticoagulant testing was positive. In addition, the dilute russell viper venom time (DRVV) was prolonged in the setting of normal PT/PTT, confirming APS diagnosis. She recovered within five days and was prescribed warfarin for chronic anticoagulation, glucocorticoids were tapered, while rituximab infusions were initiated as glucocorticoid-sparing therapy. DISCUSSION: This case highlights challenges associated with the diagnosis and management of rare simultaneous manifestations of APS. In particular, the management of DAH in this scenario is unique because unlike the glucocorticoid-responsive antibodies of ANCA-associated vasculitides, aPL are not known to cause alveolar capillaritis; therefore, the role of steroids is unclear. CONCLUSIONS: Chronic anticoagulation is an absolute requirement for long-term management of APS. Yet as this case exemplifies, in the case of concomitant DAH, administration of glucocorticoids, and subsequently glucocorticoid-sparing immunosuppression is recommended as the safest approach to avoid life-threatening hemorrhage. REFERENCE #1: Cartin-Ceba R, Peikert T, Ashrani A, Keogh K, Wylam ME, Ytterberg S, Specks U. Primary antiphospholipid syndrome-associated diffuse alveolar hemorrhage. Arthritis Care Res (Hoboken). 2014 Feb;66(2):301-10. doi: 10.1002/acr.22109. PMID: 23983016. REFERENCE #2: Stoots SA, Lief L, Erkan D. Clinical Insights into Diffuse Alveolar Hemorrhage in Antiphospholipid Syndrome. Curr Rheumatol Rep. 2019 Sep 6;21(10):56. doi: 10.1007/s11926-019-0852-7. PMID: 31493005; PMCID: PMC7102334. REFERENCE #3: Janowiak P, Sieminska A, Porzezinska M, Smolenska Z, Suchanek H, Jassem E. Difficulties in the treatment of recurring diffuse alveolar hemorrhage accompanying primary antiphospholipid syndrome: a case report and literature review. Adv Respir Med. 2018;86(3). doi: 10.5603/ARM.2018.0020. PMID: 29960279. DISCLOSURES: No relevant relationships by Eric Knott, source=Web Response no disclosure on file for Eric Lang; No relevant relationships by Claudia Saborit, source=Web Response

Effect of gene polymorphism on bleeding complications in Chinese Han patients taking warfarin

The purpose of this study was to analyse the effects of demographic factors, clinical factors, and genetic polymorphisms of related gene loci on warfarin bleeding-related complications in the Han population. Retrospective medical record review. The study cases were patients treated at the Fujian Medical University Union Hospital from March 2016 to February 2020, and all received regular warfarin anticoagulation treatment for at least 3months, and were provided the initial standard dose and stable dose of warfarin. Data were collected from 451 qualifying patients (47% male, 53% female). The average age of patients was 53.8 ± 12.2years, and the average body surface area was 1.6 ± 0.18 m2. There were nine major bleeding events and 141 minor bleeding events. In the univariate logistic analysis, the p-value of the four factors body weight, body surface area (BSA), amiodarone, and rs429358 was < 0.10. However, the final p-values for amiodarone and rs429358 were < 0.05 in the multifactorial logistic analysis. The ApoE (rs429358) gene polymorphism influences bleeding complications in Chinese Han patients treated with warfarin. The sample size of this study was relatively small; hence an international study with a larger sample size is needed in the future.

Measuring serum prothrombin in patients treated with warfarin or direct oral anticoagulants

BackgroundWarfarin therapy influences generation of γ-carboxyglutamyl (Gla) residues in prothrombin, causing reduced coagulation activity. It will leave such inactive prothrombin in serum after clot formation, resulting in serum prothrombin constituting total inactive prothrombin in these patients. MethodsAn ELISA was developed to measure biologically inactive prothrombin in serum, and applied to serum from warfarin therapy causing a decrease in Gla residues or direct oral anticoagulant (DOAC) therapy as its contrast. ResultsThe concentrations of serum prothrombin in both the warfarin and DOAC groups were higher than those in the healthy group (p < 0.01 and p < 0.001, respectively). When serum in the previous three groups was treated with barium carbonate to exclude prothrombin, which lost several Gla residues, the prothrombin concentration in the DOAC group decreased to the same level as that in the healthy group, indicating that prothrombin was obtained at a high level only in the warfarin group (p < 0.01). ConclusionsWarfarin and DOAC led to increase in serum prothrombin concentration. The reason is that DOAC decreases prothrombin recruitment during fibrin clot formation, while warfarin leads to the accumulation of inactive prothrombin, which have a decreased number of Gla residues.

Effect of Direct Oral Anticoagulants Versus Warfarin on Patency in High-Risk Bypass Patients

The use of warfarin for anticoagulation in thromboembolic disease has been the mainstay of treatment. Direct oral anticoagulants (DOACs) have shown to have equivalent anticoagulant effects, without increased bleeding risks or need for frequent monitoring. However, the role of DOACs remains unclear as an alternative to warfarin for high-risk peripheral artery disease (PAD) interventions. The purpose of this study is to evaluate the efficacy of DOACs compared to warfarin during the postoperative period in patients that underwent a high-risk lower extremity bypass (HRB).

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

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