[Interdisciplinary aspects of oral anticoagulation with NOACs in atrial fibrillation]. / Interdisziplinäre Aspekte der oralen Antikoagulation mit NOAKs bei Vorhofflimmern.

Stroke prophylaxis with non-vitamin K-dependent oral anticoagulants (NOAKs) in patients with non-valvular atrial fibrillation (nvVHF) is now firmly established in routine clinical practice. The definition of nvVHF includes the absence of a mechanical heart valve and AF not associated with moderate- or high-grade mitral valve stenosis. The management of oral anticoagulation (OAC) requires a high degree of interdisciplinarity. Not least for this reason, uncertainties are repeatedly observed in practice, which can have far-reaching consequences for the individual patient. For this reason, a committee consisting of representatives from general medicine, geriatrics, cardiology, nephrology and neurology has gathered to identify aspects of practical relevance from the various disciplines and to jointly develop practical guidelines to improve therapy safety for patients in everyday life.

Post-hospital discharge venous thromboembolism prophylaxis in medically ill patients.

There is a widely expressed concern about an unmet need for post hospitalization venous thromboembolism (VTE) prophylaxis in medically ill patients, however, physicians and hospitals have been slow to implement this measure. Recommendations against extended VTE prophylaxis in medical patients from the American Society of Hematology (ASH) in 2018 and the withholding of approval of betrixiban by the European Medicines Agency also in 2018 may have been influential in this regard. Furthermore, rivaroxaban the other drug approved for this indication in the U.S has not yet been approved in Europe. In addition, hospital administrators, those monitoring expenses in the U.S, have been reluctant to support a treatment which will mostly involve outpatients. Internal medicine physicians, hospitalists and nursing home physicians have not shared the fervor for post hospital VTE prophylaxis, whether with anticoagulants or aspirin, that their orthopedic surgery colleagues have, particularly in hip and knee arthroplasty. This is despite an increased risk of post hospital discharge thrombosis in both groups of patients. Enter hospitalized patients with COVID-19, a potentially severe medical illness with high hospitalization related thrombosis risk, and questions arise as to whether these medical patients, who are clearly more hypercoagulable during hospitalization than those in previous studies, should warrant post hospital discharge prophylaxis.

Hyperacute multi-organ thromboembolic storm in COVID-19: a case report.

Acute viral pneumonia, hypoxemic respiratory failure and severe inflammatory response are hallmarks of severe coronavirus disease 2019 (COVID-19). The COVID-19-associated inflammatory state may further lead to symptomatic thromboembolic complications despite prophylaxis. We report a 66-year-old female patient with post-mortem diagnosis of COVID-19 who presented progressive livedo racemosa, acute renal failure and myocardial injury, as well as an absence of respiratory symptoms. Transthoracic echocardiography showed severe spontaneous echo contrast in the right cardiac chambers and right-sided cardiac overload presumed to result from pulmonary microvascular thrombosis or embolism. D-dimer levels were increased. The patient developed an acute ischemic stroke and died 2 days following presentation despite therapeutic anticoagulation. Her predominantly thromboembolic presentation supports the concept of coronavirus infection of endothelial cells and hypercoagulability, or COVID-19 endotheliitis. The case we report highlights that COVID-19-associated hyperacute multi-organ thromboembolic storm may precede or present disproportionately to respiratory involvement.

Aortic thrombus in patients with severe COVID-19: review of three cases.

Coronavirus disease 2019 (COVID-19) could predispose to both venous and arterial thromboembolism, in an exaggerated immune response to the virus, especially in severe patients. Even though aortic clots are a rare entity, the pro-coagulant nature of COVID-19 is associated with thrombosis in atypical locations and should be considered in patients with severe abnormalities in coagulation parameters. We describe a series of three cases of aortic thrombi diagnosed by computerized tomography (CT) angiography in patients with confirmed SARS-CoV-2 infection.

Anticoagulation for Patients With Atrial Fibrillation and End-Stage Renal Disease on Dialysis: A National Survey.

Patients with atrial fibrillation (AF) have a significant increased risk of embolic stroke. Patients with end-stage renal disease who are on dialysis have an increased risk of both embolic stroke and bleeding. Stroke-prevention studies with the use of anticoagulation for AF patients have excluded patients on dialysis, so there remains no consensus on their management. We developed and implemented a pan-Canadian multidisciplinary survey to explore the current beliefs and practices concerning patients with AF on dialysis. We developed an online investigator-designed survey with both quantitative and qualitative responses with the use of a secure university-affiliated electronic service. The survey was distributed to physicians via the QxMD platform and directly to internal medicine, cardiology, and nephrology residency program directors for distribution to faculty members. 130 participants responded, including 46 cardiologists, 45 nephrologists, 30 general internists, and 9 other physicians. The preferred anticoagulant was warfarin. The CHADS2 score used to initiate anticoagulation was highly variable, with specialties differing in use of a CHADS2 threshold of ≥ 1 (P < 0.001) and the impact of previous transient ischemic attack/stroke (P = 0.02). Calciphylaxis history affected the decision to prescribe anticoagulation. Specialties differed in thresholds used to consider direct oral anticoagulants for dialysis patients, with nephrologists more likely to prescribe anticoagulation at higher CHADS2 scores. Our survey demonstrated significant heterogeneity of anticoagulation use for stroke prevention in patients with AF on dialysis. Physician specialty and patient risk profiles contributed to the observed variability. This study reemphasises the need for clinical trials, large observational studies, and consensus guidelines to address evident equipoise.

Questions and Answers on Practical Thrombotic Issues in SARS-CoV-2 Infection: A Guidance Document from the Italian Working Group on Atherosclerosis, Thrombosis and Vascular Biology.

In patients with coronavirus disease 2019 (COVID-19), the prevalence of pre-existing cardiovascular diseases is elevated. Moreover, various features, also including pro-thrombotic status, further predispose these patients to increased risk of ischemic cardiovascular events. Thus, the identification of optimal antithrombotic strategies in terms of the risk-benefit ratio and outcome improvement in this setting is crucial. However, debated issues on antithrombotic therapies in patients with COVID-19 are multiple and relevant. In this article, we provide ten questions and answers on risk stratification and antiplatelet/anticoagulant treatments in patients at risk of/with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection based on the scientific evidence gathered during the pandemic.

Underuse of oral anticoagulants in privately insured patients with atrial fibrillation: A population being targeted by the IMplementation of a randomized controlled trial to imProve treatment with oral AntiCoagulanTs in patients with Atrial Fibrillation (IMPACT-AFib).

BACKGROUND: Many studies showing underuse of oral anticoagulants (OACs) in patients with atrial fibrillation (AF) predated the advent of the non-vitamin K antagonist OACs. We retrospectively examined use of OACs in a large commercially insured population. METHODS: Administrative claims data from 4 research partners participating in FDA-Catalyst, a program of the Sentinel Initiative, were queried in September 2017. Patients were included if they were ≥30 years old with ≥365 days of medical/pharmacy coverage, and had ≥2 diagnosis codes for AF, a CHA2DS2-VASc score ≥2, absence of contraindications to OAC use, and no evidence of OAC use in the 365 days before the index AF diagnosis. The main outcome measures of the current analysis were rates of OAC use in the prior 12 months of cohort identification and factors associated with non-use. RESULTS: A total of 197,806 AF patients met the eligibility criteria prior to assessment of OAC treatment. Of these, 179,580 (91%) patients were ≥65 years old and 73,286 (37%) patients were ≥80 years old. Half of the patients (98,903) were randomized to the early intervention arm in the IMPACT-AFib trial and constitute the cohort for this analysis. Of these, 32,295 (33%) had no evidence of OAC use in the prior 12 months. Compared with patients with evidence of OAC use in the prior 12 months, patients without OAC use were more likely to be ≥80 years old, women, and have a history of anemia (51% vs 47%) and less likely to have diabetes (41% vs 44%), history of stroke or TIA (15% vs 19%), and history of heart failure (39% vs 48%). CONCLUSIONS: Despite a high risk of stroke, one-third of privately insured patients with AF and no obvious contraindications to an OAC were not treated with an OAC. There is an unmet need for evidence-based interventions that could lead to greater use of OACs in patients with AF at risk for stroke.

Anticoagulation, Bleeding, Mortality, and Pathology in Hospitalized Patients With COVID-19.

BACKGROUND: Thromboembolic disease is common in coronavirus disease-2019 (COVID-19). There is limited evidence on the association of in-hospital anticoagulation (AC) with outcomes and postmortem findings. OBJECTIVES: The purpose of this study was to examine association of AC with in-hospital outcomes and describe thromboembolic findings on autopsies. METHODS: This retrospective analysis examined the association of AC with mortality, intubation, and major bleeding. Subanalyses were also conducted on the association of therapeutic versus prophylactic AC initiated ≤48 h from admission. Thromboembolic disease was contextualized by premortem AC among consecutive autopsies. RESULTS: Among 4,389 patients, median age was 65 years with 44% women. Compared with no AC (n = 1,530; 34.9%), therapeutic AC (n = 900; 20.5%) and prophylactic AC (n = 1,959; 44.6%) were associated with lower in-hospital mortality (adjusted hazard ratio [aHR]: 0.53; 95% confidence interval [CI]: 0.45 to 0.62 and aHR: 0.50; 95% CI: 0.45 to 0.57, respectively), and intubation (aHR: 0.69; 95% CI: 0.51 to 0.94 and aHR: 0.72; 95% CI: 0.58 to 0.89, respectively). When initiated ≤48 h from admission, there was no statistically significant difference between therapeutic (n = 766) versus prophylactic AC (n = 1,860) (aHR: 0.86; 95% CI: 0.73 to 1.02; p = 0.08). Overall, 89 patients (2%) had major bleeding adjudicated by clinician review, with 27 of 900 (3.0%) on therapeutic, 33 of 1,959 (1.7%) on prophylactic, and 29 of 1,530 (1.9%) on no AC. Of 26 autopsies, 11 (42%) had thromboembolic disease not clinically suspected and 3 of 11 (27%) were on therapeutic AC. CONCLUSIONS: AC was associated with lower mortality and intubation among hospitalized COVID-19 patients. Compared with prophylactic AC, therapeutic AC was associated with lower mortality, although not statistically significant. Autopsies revealed frequent thromboembolic disease. These data may inform trials to determine optimal AC regimens.

Clinical characteristics and treatment patterns of patients with venous thromboembolism (VTE) transitioning from hospital to post-discharge settings.

OBJECTIVE: This study examined anticoagulant use during and after a hospital encounter for venous thromboembolism (VTE), a transition of care largely uncharacterized in the literature. METHODS: Adults with a VTE diagnosis code during a hospital encounter (emergency department [ED], observation area [OBS], or inpatient hospital [IP]) from January 2012 to August 2017 were identified in an electronic health records database. The first such hospital encounter was defined as the index VTE encounter. Patients were linked to a claims database and required to be continuously enrolled for six months before the index admission date through six months after the index discharge date. Anticoagulants administered during the index VTE encounter and filled on or within 30 days of discharge were summarized descriptively overall, and by the type of index VTE encounter (IP, No IP) and anticoagulants administered during the index VTE encounter. RESULTS: Among 2,968 eligible patients, mean (SD) age was 64 (16) years, 51% were female, 67% had an IP index VTE encounter, and 77% received anticoagulation therapy during the index VTE encounter. In total, 60% filled a prescription order for anticoagulant within 30 days post-discharge. Of those who received a direct oral anticoagulant (DOAC), warfarin, or parenteral anticoagulant only during the index VTE encounter, 74%, 69%, and 34%, respectively, filled a prescription for the same anticoagulant post-discharge. Patients treated with a DOAC or warfarin during an ED or OBS VTE encounter without a subsequent inpatient hospitalization were more likely to remain on the same anticoagulation therapy post-discharge than those with an inpatient hospitalization (81% vs 69% for DOAC and 75% vs 68% for warfarin). CONCLUSIONS: Many patients treated with anticoagulation therapy during a VTE hospital encounter did not fill a prescription for an anticoagulant within 30 days post-discharge, highlighting an opportunity for improved management of care transitions in this patient population.

[Direct oral anticoagulants: In which indications? Which one to prescribe? For or against their use in frail patients and in atypical cases? Which monitoring and management haemorrhage complications?] / Anticoagulants oraux directs : dans quelles indications ? Lequel prescrire ? Pour ou contre chez les personnes fragiles et dans les situations atypiques ? Quelle surveillance et gestion des accidents hémorragiques ?

Since their approval, the direct oral anticoagulants have been widely used in the management of venous thromboembolism, for stroke and systemic embolism prevention in non valvular atrial fibrillation, and in venous thromboembolism prophylaxis after surgical hip or knee replacement. Because they are easy to use, with oral fixed doses and no biological monitoring need, they are more and more prescribed. New indications are rising in cancer associated thrombosis in France beyond the 6 first months of treatment, and to prevent cardiovascular events after an acute coronary syndrome, or in stable coronary or peripheral arterial disease in Europe. The efficacity and safety of direct oral anticoagulants in frail patients or in unusual pathological contexts are not entirely known, but further data are coming and will probably bring new answers.

Transfusion Thresholds for Adult Respiratory Extracorporeal Life Support: An Expert Consensus Document.

Severe acute respiratory distress syndrome (ARDS) can complicate novel pandemic coronavirus disease (COVID-19). Extracorporeal life support (ECLS) represents the final possible rescue strategy. Variations in practice, combined with a paucity of rigourous guidelines, may complicate blood-product resource availability and allocation during a pandemic. We conducted a literature review around venovenous extracorporeal membrane oxygenation (VV-ECMO) transfusion practices for platelets, packed red blood cells, fresh frozen plasma, prothrombin complex concentrate, and antithrombin. Pertinent society guidelines were examined, and the practice of Canadian ECLS experts was sampled through an environmental scan. This paper represents a synthesis of these explorations, combined with input from the Canadian Cardiovascular Critical Care (CANCARE) Society, Canadian Society of Cardiac Surgeons, and the Canadian Critical Care Society. We offer a pragmatic guidance document for restrictive transfusion thresholds in nonbleeding patients on VV-ECMO, which may attenuate transfusion-related complications and simultaneously shield national blood product inventory from strain during pandemic-induced activation of the National Plan for the Management of Shortages of Labile Blood Components.

Draft genome of the European medicinal leech Hirudo medicinalis (Annelida, Clitellata, Hirudiniformes) with emphasis on anticoagulants.

The European medicinal leech has been used for medicinal purposes for millennia, and continues to be used today in modern hospital settings. Its utility is granted by the extremely potent anticoagulation factors that the leech secretes into the incision wound during feeding and, although a handful of studies have targeted certain anticoagulants, the full range of anticoagulation factors expressed by this species remains unknown. Here, we present the first draft genome of the European medicinal leech, Hirudo medicinalis, and estimate that we have sequenced between 79-94% of the full genome. Leveraging these data, we searched for anticoagulation factors across the genome of H. medicinalis. Following orthology determination through a series of BLAST searches, as well as phylogenetic analyses, we estimate that fully 15 different known anticoagulation factors are utilized by the species, and that 17 other proteins that have been linked to antihemostasis are also present in the genome. We underscore the utility of the draft genome for comparative studies of leeches and discuss our results in an evolutionary context.

Treatment of Venous Thromboembolism in Special Populations with Direct Oral Anticoagulants.

As a result of the successful completion of their respective phase III studies compared with vitamin K antagonists (VKAs), four direct oral anticoagulants (DOACs) have been approved for the treatment and secondary prevention of venous thromboembolism (VTE). These DOACs-apixaban, dabigatran, edoxaban, and rivaroxaban-have subsequently seen a steady uptake among clinicians since their approval. Despite the suitability of DOACs for a broad range of patients, they are not appropriate in certain situations, whereas in others they require additional considerations such as dose reductions. Subanalyses of phase III trials and studies on specific VTE patient populations have been conducted to evaluate the safety and efficacy of the DOACs in a broad range of settings, such as patients with renal impairment, patients with cancer, patients of childbearing potential, patients with multiple comorbidities and pediatric patients. Furthermore, many recent guidance documents from important hematological societies and other specialists have incorporated several of these developments. These documents also identify the patients for whom DOACs are not suitable and where traditional anticoagulation options such as heparins or VKAs should be considered instead. This review provides an overview of key VTE patient subgroups, the clinical evidence supporting the use of anticoagulation in these patients, and a discussion of the most appropriate approaches to their management, including considerations such as dosing, acute and extended treatment durations, and DOAC selection.

Antiphospholipid syndrome and challenges with direct oral anticoagulants.

Direct oral anticoagulants have become the mainstay of the management of venous thromboembolism and atrial fibrillation, and long-term anticoagulation is indicated for those at high risk of further thrombotic events. This includes patients diagnosed with antiphospholipid syndrome, for whom the 'triple positive' laboratory combination of lupus anticoagulant, ß2-glycoprotein-1 and anti-cardiolipin antibodies signify those at greatest risk. Data from meta-analysis and randomised control trials have raised the concern that direct oral anticoagulants may be less effective than vitamin K antagonists for the prevention of thrombosis in patients with thrombotic antiphospholipid syndrome, particularly those with the triple positive profile. This article reviews the diagnosis of thrombotic antiphospholipid syndrome, strategies for testing without interruption of anticoagulation, evidence concerning the safety of direct oral anticoagulants in this setting, and the implications for current investigation and management of unprovoked venous thromboembolism.

Factors Associated With the Choice of Oral Anticoagulant Class in the Older Patients: An Observational Study.

AIM: Oral anticoagulants are the first-line drugs for treating thrombotic disorders related to nonvalvular atrial fibrillation and for treating deep vein thrombosis, diseases that increase in prevalence with age. Older patients have a greater risk of thrombotic and hemorrhagic events and are more prone to drug interactions. Given this backdrop, we wanted to determine the factors associated with the prescription of direct oral anticoagulants and vitamin K antagonists in older patients. METHODS: We performed a cross-sectional observational study using a hospital prescription database. The study population consists of 405 older patients who were given oral anticoagulants. The 2 variables of interest were the prescription of 1 of the 2 classes of oral anticoagulants (direct oral anticoagulants vs vitamin K antagonists) and appropriateness of oral anticoagulant prescribing according to Summary of Product Characteristics (potentially inappropriate vs appropriate). RESULTS: The factors associated with direct oral anticoagulant prescribing were the female gender (odds ratio [OR]: 1.87, 95% confidence interval [CI]: 1.22-2.88) and initiation during hospital stay (OR: 2.56, 95% CI: [1.52-4.32]). Stage 4 and 5 chronic kidney diseases (OR: 0.39, 95% CI: [0.19-0.79] and OR: 0.07, 95% CI: [0.01-0.53]) were factors favoring vitamin K antagonist prescription. Being 90 years of age or more (OR: 2.05, 95% CI: [1.06-3.98]) was a factor for potentially inappropriate anticoagulant prescribing. The gastroenterology department (OR: 2.91, 95% CI: [1.05-8.11]) was associated with potentially inappropriate anticoagulant prescribing. CONCLUSIONS: Direct oral anticoagulants are the drugs of choice for anticoagulant treatment, including in older adults. The female gender and the initiation during hospital stay increased the chances of being prescribed a direct oral anticoagulant in older adults. Stage 4 and 5 chronic kidney disease increased the likelihood of having a vitamin K antagonist prescribed. Our study also revealed a persistence of potentially inappropriate oral anticoagulant prescriptions in older patients.

Guidelines for the Management of Adult Acute and Acute-on-Chronic Liver Failure in the ICU: Cardiovascular, Endocrine, Hematologic, Pulmonary, and Renal Considerations.

OBJECTIVES: To develop evidence-based recommendations for clinicians caring for adults with acute or acute on chronic liver failure in the ICU. DESIGN: The guideline panel comprised 29 members with expertise in aspects of care of the critically ill patient with liver failure and/or methodology. The Society of Critical Care Medicine standard operating procedures manual and conflict-of-interest policy were followed throughout. Teleconferences and electronic-based discussion among the panel, as well as within subgroups, served as an integral part of the guideline development. SETTING: The panel was divided into nine subgroups: cardiovascular, hematology, pulmonary, renal, endocrine and nutrition, gastrointestinal, infection, perioperative, and neurology. INTERVENTIONS: We developed and selected population, intervention, comparison, and outcomes questions according to importance to patients and practicing clinicians. For each population, intervention, comparison, and outcomes question, we conducted a systematic review aiming to identify the best available evidence, statistically summarized the evidence whenever applicable, and assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence to decision framework to facilitate recommendations formulation as strong or conditional. We followed strict criteria to formulate best practice statements. MEASUREMENTS AND MAIN RESULTS: In this article, we report 29 recommendations (from 30 population, intervention, comparison, and outcomes questions) on the management acute or acute on chronic liver failure in the ICU, related to five groups (cardiovascular, hematology, pulmonary, renal, and endocrine). Overall, six were strong recommendations, 19 were conditional recommendations, four were best-practice statements, and in two instances, the panel did not issue a recommendation due to insufficient evidence. CONCLUSIONS: Multidisciplinary international experts were able to formulate evidence-based recommendations for the management acute or acute on chronic liver failure in the ICU, acknowledging that most recommendations were based on low-quality indirect evidence.

Total Thrombus-Formation Analysis System can Predict 1-Year Bleeding Events in Patients with Coronary Artery Disease.

AIMS: The assessment of bleeding risk in patients with coronary artery disease (CAD) is clinically important. We recently developed the Total Thrombus-Formation Analysis System (T-TAS) for the quantitative analysis of thrombus formation using microchips with thrombogenic surfaces. Here, we assessed the utility of T-TAS parameters in predicting 1-year bleeding events in patients with CAD. METHODS: The study subjects were 561 consecutive patients who underwent coronary angiography (CAG) between August 2013 and September 2016 for suspected CAD. Blood samples collected at the time of CAG were used for T-TAS to compute the area under the curve (AUC) (AR10-AUC30) in the AR chip. Patients were divided into three groups according to AR10-AUC30 (low: ≤ 1603, intermediate, and high: ＞1765, n=187 each). One-year bleeding events were defined by the Platelet Inhibition and Patient Outcomes criteria. RESULTS: Bleeding occurred in 21 (3.7%) patients and was classified as major (8 [1.4%]) and minor (13 [2.3%]). The AR10-AUC30 levels were significantly lower in the bleeding group than the non-bleeding group (median [interquartile range] 1590 [1442-1734] vs. 1687 [1546-1797], p=0.04). Univariate Cox regression analysis demonstrated that low AR10-AUC30 , high prothrombin time-international normalized ratio levels, and diabetes correlated with bleeding events. Multivariate Cox regression analysis identified low AR10-AUC30 levels as a significant determinant of bleeding events. Kaplan-Meier survival curves showed a higher rate of bleeding events in the low than the high AR10-AUC30 group (p=0.007). CONCLUSIONS: The results highlight the potential usefulness of the AR10-AUC30 levels in the prediction of 1-year bleeding events in patients with CAD treated with various antithrombotic therapies.