Expanding the genetic and clinical spectrum of Tatton-Brown-Rahman syndrome in a series of 24 French patients.

BACKGROUND: Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as DNA methyltransferase 3 alpha (DNMT3A)-overgrowth syndrome (DOS), was first described by Tatton-Brown in 2014. This syndrome is characterised by overgrowth, intellectual disability and distinctive facial features and is the consequence of germline loss-of-function variants in DNMT3A, which encodes a DNA methyltransferase involved in epigenetic regulation. Somatic variants of DNMT3A are frequently observed in haematological malignancies, including acute myeloid leukaemia (AML). To date, 100 individuals with TBRS with de novo germline variants have been described. We aimed to further characterise this disorder clinically and at the molecular level in a nationwide series of 24 French patients and to investigate the correlation between the severity of intellectual disability and the type of variant. METHODS: We collected genetic and medical information from 24 individuals with TBRS using a questionnaire released through the French National AnDDI-Rares Network. RESULTS: Here, we describe the first nationwide French cohort of 24 individuals with germline likely pathogenic/pathogenic variants in DNMT3A, including 17 novel variants. We confirmed that the main phenotypic features were intellectual disability (100% of individuals), distinctive facial features (96%) and overgrowth (87%). We highlighted novel clinical features, such as hypertrichosis, and further described the neurological features and EEG results. CONCLUSION: This study of a nationwide cohort of individuals with TBRS confirms previously published data and provides additional information and clarifies clinical features to facilitate diagnosis and improve care. This study adds value to the growing body of knowledge on TBRS and broadens its clinical and molecular spectrum.

Efforts to Better Characterize "Antiphospholipid Antibody Nephropathy" for the 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria: Renal Pathology Subcommittee Report.

OBJECTIVE: Antiphospholipid antibody (aPL) nephropathy (-N) can be challenging to recognize due to a lack of established classification or diagnostic criteria. As part of efforts to develop new antiphospholipid syndrome (APS) classification criteria (CC), the APS CC Renal Pathology Subcommittee aimed to better characterize the entity of aPL-N. METHODS: We used a 4-pronged approach that included (1) administering Delphi surveys to worldwide APS physicians to generate aPL-N terminology; (2) conducting a literature review to demonstrate the association of nephropathy with aPL and identify published aPL-N histopathological terminology and descriptions; (3) evaluating aPL-N terminology used in renal biopsy reports from an international patient registry; and (4) evaluating proposed kidney pathologic features for aPL-N by assessment of international Renal Pathology Society (RPS) members. RESULTS: After completing our metaanalysis demonstrating an association between nephropathy and aPL, we used Delphi surveys, a literature review, and international renal biopsy reports to develop a preliminary definition of aPL-N. The preliminary definition included include specific terms associated with acute (ie, thrombotic microangiopathy in glomeruli or arterioles/arteries) and chronic (ie, organized arterial or arteriolar microthrombi with or without recanalization, organized glomerular thrombi, fibrous and fibrocellular [arterial or arteriolar] occlusions, focal cortical atrophy with or without thyroidization, and fibrous intimal hyperplasia) lesions. Most RPS survey respondents agreed with this terminology and the importance of knowing aPL results for histopathological diagnosis. CONCLUSION: Our results support the inclusion of aPL-N in the 2023 American College of Rheumatology/European Alliance of Associations for Rheumatology APS CC, and provide the most widely accepted terminology to date for both acute and chronic pathologic lesions of aPL-N.

Thrombin Generation Assay in Antiphospholipid Antibodies Positive Subjects as a Personalized Thrombotic Risk Assessment: State of the Art and Perspectives.

PURPOSE OF THE REVIEW: Thrombotic risk assessment in antiphospholipid positive (aPL +) subjects is a major challenge, and the study of in vitro thrombin generation (thrombin generation assays (TGA)) could provide useful information. Activated protein C (APC) sensitivity is involved in thrombotic events in antiphospholipid syndrome patients. We summarized methods used to assess APC sensitivity with TGA and evaluated the prognostic role of APC resistance through literature search. RECENT FINDINGS: APC resistance induced by aPL is a complex pathway. Several cross-sectional studies assessed APC sensitivity to understand thrombotic event mechanisms in aPL + subjects. Only one prospective cohort had investigated the prognostic impact of APC resistance in aPL + subjects, with a positive and significant correlation between APC sensitivity and the risk of thrombosis during the follow up (hazard ratio, 6.07 [95% CI, 1.69-21.87]). APC resistance assessed with TGA could be associated with thrombotic events in aPL + subjects.

2023 ACR/EULAR antiphospholipid syndrome classification criteria.

OBJECTIVE: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. METHODS: This international multidisciplinary initiative included four phases: (1) Phase I, criteria generation by surveys and literature review; (2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; (3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and (4) Phase IV, validation using independent adjudicators' consensus as the gold standard. RESULTS: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into six clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and two laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-ß2-glycoprotein I antibodies). Patients accumulating at least three points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria vs the 2006 revised Sapporo classification criteria had a specificity of 99% vs 86%, and a sensitivity of 84% vs 99%. CONCLUSION: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.

A new pro-thrombotic mechanism of neutrophil extracellular traps in antiphospholipid syndrome: impact on activated protein C resistance.

OBJECTIVES: In APS, precise evaluation of thrombotic risk is a major challenge. Different players, such as activated protein C (APC) resistance or neutrophil extracellular traps (NETs) contribute to the risk of thrombosis. Nevertheless, no study has investigated the interaction between these actors. The main objective of this study was to investigate the relation between NETs and APC resistance. METHODS: We designed a cross-sectional study including APS/antiphospholipid antibodies (aPL) patients and patients with autoimmune diseases (AID). We performed thrombin generation tests without and with APC to determine APC resistance. To evaluate circulating NETs, we measured plasma levels of MPO-DNA complexes and cell-free DNA with ELISA. RESULTS: We recruited 117 patients with definite APS/aPL or AID. We found a positive correlation between NETs and APC resistance, in APS patients and specifically in patients with high thrombotic risk, displaying LA or positivity of all three aPL tests (triple+), or anti-domain I IgG (aDI+). All these patient subgroups had increased NETs concentrations and APC resistance. As the risk profile for thrombosis increased, the relationship between NETs and APC resistance was stronger. CONCLUSION: We have shown that NETs participate in the hypercoagulable state of APS patients by contributing to APC resistance, in particular in high-risk patients. In these most at-risk patients, a targeted action on NETs could reduce APC resistance and constitute a new therapeutic approach in the treatment of APS patients in addition to antithrombotic therapy.

Manual rotation of occiput posterior or transverse positions: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: The primary objective of this systematic review was to assess the association between spontaneous vaginal delivery and manual rotation during labor for occiput posterior or transverse positions. Our secondary objective was to assess maternal and neonatal outcomes. DATA SOURCES: An electronic search of PubMed, EMBASE, ClinicalTrials.gov, and the Cochrane Register of Controlled Trials covered the period from January 2000 to September 2021, without language restrictions. STUDY ELIGIBILITY CRITERIA: The eligibility criteria included all randomized trials with singleton pregnancies at ≥37 weeks of gestation comparing the manual rotation groups with the control groups. The primary outcome was the rate of spontaneous vaginal delivery. Additional secondary outcomes were rate of occiput posterior position at delivery, operative vaginal delivery, cesarean delivery, postpartum hemorrhage, obstetrical anal sphincter injury, prolonged second stage of labor, shoulder dystocia, neonatal acidosis, and phototherapy. Subgroup analyses were performed according to types of position (occiput posterior or occiput transverse), techniques used (whole-hand or digital rotation), and parity (nulliparous or parous). METHODS: The quality of each study was evaluated with the revised Cochrane risk-of-bias tool for randomized trials, known as RoB 2. The meta-analysis used random-effects models depending on their heterogeneity, and risks ratios were calculated for dichotomous outcomes. RESULTS: Here, 7 of 384 studies met the inclusion criteria and were selected. They included 1402 women: 704 in the manual rotation groups and 698 in the control groups. Manual rotation was associated with a higher rate of spontaneous vaginal delivery: 64.9% vs 59.5% (risk ratio, 1.09; 95% confidence interval, 1.03-1.16; P=.005; 95% prediction interval, 0.90-1.32). This association was no longer significant after stratification by parity or technique used. Manual rotation was associated with spontaneous vaginal delivery only for the occiput posterior position (risk ratio, 1.08; 95% confidence interval, 1.01-1.15). Furthermore, it was associated with a reduction in occiput posterior or transverse positions at delivery (risk ratio, 0.64; 95% confidence interval, 0.48-0.87) and episiotomies (risk ratio, 0.84; 95% confidence interval, 0.71-0.98). The groups did not differ significantly for cesarean deliveries, operative vaginal deliveries, or neonatal outcomes. CONCLUSION: Manual rotation increased the rate of spontaneous vaginal delivery.

Antiphospholipid syndrome in patients over 65 years: A comparative study of clinical and biological features and thrombotic relapses.

OBJECTIVE: The aim of the study was to describe clinical and biological characteristics and thrombotic relapses of patients diagnosed with antiphospholipid syndrome (APS) after the age of 65 years, in comparison with patients diagnosed with APS before 65. METHODS: This retrospective multicenter study was performed to 2005 from 2017 and included patients diagnosed with APS after the age of 65 years, in accordance with Sydney criteria. We compared these patients with APS patients diagnosed before the age of 65 years, and with control thrombotic patients older than 65 years. RESULTS: Fifty-eight APS patients over the age of 65 years were compared to 127 APS patients aged less than 65 and to 58 controls. In elderly APS versus younger APS, there was a male predominance (58.6% vs 36.2% p = .001); myocardial infarction and lower limb deep vein thrombosis (LLDVT) were more frequent in elderly, respectively, 12.1% versus 1.6% (p = .005), and 44.8% versus 29.9% (p = .048). Anticardiolipin antibody (aCL) IgM was more frequently found in old patients compared to younger patients (33.9% vs 18.1%, p = .02), contrary to lupus anticoagulant (LAC) (52.8% vs 66.9%, p = .02). Older patients were more often diagnosed with single positive APS (82.8% vs 59.8% p = .002). The thrombotic relapse free survival was lower in elderly APS patients (p = .044) compared to younger APS. Elderly APS patients had more recurrent arterial and venous thrombosis (p = .03) and had poorer overall survival (p = .004) than elderly controls. CONCLUSION: In this study, APS was different in patients aged more than 65 years, with a male predominance and more myocardial infarctions and LLDVT at diagnosis. Single antiphopholipid positivity and aCL IgM were more frequent in older patients. Older patient with APS had more thrombotic recurrence during follow-up. Compared to elderly controls, elderly APS patients had more thrombosis recurrences and poorer survival.

Risk of livedo with antiphospholipid antibodies in patients with systemic lupus erythematosus: A systematic review and meta-analysis.

BACKGROUND: Livedo is a well-known skin condition in patients with systemic lupus erythematosus (SLE) which correspond to small vessels involvement. The influence of antiphospholipid antibodies (aPL) on the occurrence of livedo is controversial. The aim of our study was to estimate the risk of livedo associated with aPL in patients with SLE. METHODS: We conducted a systematic review and meta-analysis of the literature from 1977 to 2021 to estimate the risk of livedo in SLE patients according to different aPL profiles. Data sources were PubMed, Embase, Cochrane Library, hand search, and reference lists of studies. Studies were selected if they included SLE patients with descriptions of the exposure to aPL and the outcome (livedo). Two independent investigators assessed study eligibility, quality, and extracted patient characteristics from each study as well as exposure (aPL) and outcome (livedo). Risk estimates were pooled using random effects models and sensitivity analyses. For all stages of the meta-analysis, we followed the PRISMA guidelines. PROSPERO registration number: CRD42015027377. RESULTS: Of the 2,355 articles identified, 27 were included with a total of 4,810 SLE patients. The frequency of livedo was 25.5% in aPL-positive patients and 13.3% in aPL-negative patients. The overall Odds Ratio (OR) for livedo in aPL-positive patients compared to aPL-negative patients was 2.91 (95% CI; 2.17-3.90). The risk of livedo was significantly increased for most of aPL subtypes, including lupus anticoagulant (LA) (OR = 4.45 [95% CI; 2.21-8.94]), IgG anticardiolipin (OR = 3.95 [95% CI; 2.34-6.65]), and IgG anti-ß2-glycoprotein 1 (OR = 3.49 [95% CI; 1.68-7.27]). CONCLUSIONS: We demonstrated in this meta-analysis an excess risk of livedo in aPL-positive SLE patients compared to aPL-negative patients. For daily practice, in patients with SLE, livedo associated with aPL could correspond to a peculiar group of patients with small vessel disease. Livedo could be a good candidate for inclusion in future classification criteria for antiphospholipid syndrome.

Ophthalmologic manifestations in patients with antiphospholipid antibodies: Beware of iatrogenic complications.

BACKGROUND: Antiphospholipid syndrome (APS) is characterized by several clinical manifestations such as venous and arterial thrombosis associated with persistent antiphospholipid antibodies (aPL). Several studies confirmed that retinal vein occlusion was the most common APS ocular manifestation. The purpose of this study was to identify ophthalmologic manifestations in a homogeneous cohort of well-defined persistently aPL-positive patients and to determine variables associated with these manifestations. METHODS: APL-positive patients were selected from two research programs. All ophthalmologic manifestations including those related to APS were recorded. RESULTS: A total of 117 patients were included and 10 of them had APS-related ophthalmologic manifestations (glaucoma, hydroxychloroquine-related maculopathy, anterior acute uveitis, anterior ischemic optic neuropathy). Systemic Lupus Erythematosus (SLE) (OR = 3.4[95%CI; 0.9-12.7), corticosteroids (OR = 9.0 [95%CI; 2.2-37.7]) and aPL-related nephropathy (OR = 7.1 [95%CI; 1.7-30.0]) were significatively associated with the risk of APS-related ophthalmologic manifestations. CONCLUSION: Most of ocular manifestations in this study were iatrogenic related to corticosteroids or hydroxychloroquine. Patients with SLE, small vessel thrombosis in general, or with aPL-related nephropathy in particular, seemed at higher risk to develop APS-related ophthalmologic manifestations thus deserving adequate monitoring.

COVID-19 and antiphospholipid antibodies: A position statement and management guidance from AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION).

Coronavirus disease 2019 (COVID-19) is associated with a high rate of thrombosis. Prolonged activated partial thromboplastin times (aPTT) and antiphospholipid antibodies (aPL) are reported in COVID-19 patients. The majority of publications have not reported whether patients develop clinically relevant persistent aPL, and the clinical significance of new aPL-positivity in COVID-19 is currently unknown. However, the reports of aPL-positivity in COVID-19 raised the question whether common mechanisms exist in the pathogenesis of COVID-19 and antiphospholipid syndrome (APS). In both conditions, thrombotic microangiopathy resulting in microvascular injury and thrombosis is hypothesized to occur through multiple pathways, including endothelial damage, complement activation, and release of neutrophil extracellular traps (NETosis). APS-ACTION, an international APS research network, created a COVID-19 working group that reviewed common mechanisms, positive aPL tests in COVID-19 patients, and implications of COVID-19 infection for patients with known aPL positivity or APS, with the goals of proposing guidance for clinical management and monitoring of aPL-positive COVID-19 patients. This guidance also serves as a call and focus for clinical and basic scientific research.

Systematic Review of Antiphospholipid Antibodies in COVID-19 Patients: Culprits or Bystanders?

PURPOSE OF REVIEW: COVID-19 patients have a procoagulant state with a high prevalence of thrombotic events. The hypothesis of an involvement of antiphospholipid antibodies (aPL) has been suggested by several reports. Here, we reviewed 48 studies investigating aPL in COVID-19 patients. RECENT FINDINGS: Prevalence of Lupus Anticoagulant (LA) ranged from 35% to 92% in ICU patients. Anti-cardiolipin (aCL) IgG and IgM were found in up to 52% and up to 40% of patients respectively. Anti-ß2-glycoprotein I (aß2-GPI) IgG and IgM were found in up to 39% and up to 34% of patients respectively. Between 1% and 12% of patients had a triple positive aPL profile. There was a high prevalence of aß2-GPI and aCL IgA isotype. Two cohort studies found few persistent LA but more persistent solid phase assay aPL over time. aPL determination and their potential role is a real challenge for the treatment of this disease.

E-health education interventions on HbA1c in patients with type 1 diabetes on intensive insulin therapy: A systematic review and meta-analysis of randomized controlled trials.

AIMS: Patient-centered education improves glycemic control in subjects with type 1 diabetes (T1D). E-health technologies are widely used to support medical decision-making, patient advising or teleconsultations; however, the active participation of a patient is missing. Challenges remain whether e-health education can be effectively incorporated into clinical pathways. The purpose of the study was to examine the effects of e-health education, compared to standard care, on HbA1c. MATERIAL AND METHODS: We conducted a literature search (EMBASE, MEDLINE, The Cochrane Library and Web of Science) up to February 2018 for randomized controlled trials (RCTs) of Internet-/ mobile application-based educational interventions, with the active involvement of patients, provided in addition to, or substituting usual care in patients with T1D on intensive insulin therapy. The primary outcome was the standardized difference in means (SDM) of HbA1c change from baseline between intervention and comparator groups. RESULTS: Eight RCTs involving 757 subjects were included on 6335 screened citations. After excluding two trials with a high risk of bias from the meta-analysis, the HbA1c change from baseline did not significantly differ between intervention and comparator groups (SDM = -0.154, 95% CI: -0.335 to 0.025; P = 0.01, random-effect model). The number of studies is limited with a relatively short duration. Reporting of educational outcomes was not rigorous. CONCLUSIONS: The effect of e-health educational interventions on HbA1c in patients with T1D is comparable to the standard care. This review highlights the need for further well-designed RCTs that will investigate the opportunities of incorporating e-health education into clinical pathways.

Cluster analysis for the identification of clinical phenotypes among antiphospholipid antibody-positive patients from the APS ACTION Registry.

OBJECTIVE: This study aimed to use cluster analysis (CA) to identify different clinical phenotypes among antiphospholipid antibodies (aPL)-positive patients. METHODS: The Alliance for Clinical Trials and International Networking (APS ACTION) Registry includes persistently positive aPL of any isotype based on the Sydney antiphospholipid syndrome (APS) classification criteria. We performed CA on the baseline characteristics collected retrospectively at the time of the registry entry of the first 500 patients included in the registry. A total of 30 clinical data points were included in the primary CA to cover the broad spectrum of aPL-positive patients. RESULTS: A total of 497 patients from international centres were analysed, resulting in three main exclusive clusters: (a) female patients with no other autoimmune diseases but with venous thromboembolism (VTE) and triple-aPL positivity; (b) female patients with systemic lupus erythematosus, VTE, aPL nephropathy, thrombocytopaenia, haemolytic anaemia and a positive lupus anticoagulant test; and (c) older men with arterial thrombosis, heart valve disease, livedo, skin ulcers, neurological manifestations and cardiovascular disease (CVD) risk factors. CONCLUSIONS: Based on our hierarchical cluster analysis, we identified different clinical phenotypes of aPL-positive patients discriminated by aPL profile, lupus or CVD risk factors. Our results, while supporting the heterogeneity of aPL-positive patients, also provide a foundation to understand disease mechanisms, create new approaches for APS classification and ultimately develop new management approaches.

Health-Related Quality of Life in Antiphospholipid Syndrome: Current Knowledge and Future Perspectives.

PURPOSE OF REVIEW: Antiphospholipid syndrome (APS) is a chronic autoimmune disease that can be seen as a burden, with consequences on patients' daily life. Health has traditionally been measured using measures of morbidity or mortality. Health-related quality of life (HRQoL) is a concept that includes quality of life through physical, mental, and social domains. As in other autoimmune diseases, HRQoL has been investigated in patients with APS. Here, we provide a comprehensive review of the current knowledge of the assessment of HRQoL in APS. RECENT FINDINGS: APS patients have an impaired HRQoL compared with the general population. The presence of systemic lupus erythematosus (SLE) in APS patients is associated with a worse HRQoL than in patients without SLE. Several determinants of HRQoL impairment in APS have been identified: age, gender, history of arterial thrombosis, organ damage, lack of social support and treatments. This review highlights the negative impact of thrombosis on APS patients' HRQoL that should not be neglected. Besides, there is a need for a better strategy of communication and information, in order to improve HRQoL in APS.

New Insights into the Use of Direct Oral Anticoagulants in Non-high Risk Thrombotic APS Patients: Literature Review and Subgroup Analysis from a Meta-analysis.

PURPOSE OF REVIEW: The efficacy of direct oral anticoagulants (DOACs) in antiphospholipid syndrome (APS) is discussed. Results from randomized controlled trials are available. It has been stated that a history of arterial thrombosis and triple positivity was associated with a higher risk of thrombosis in APS patients treated with DOACs. However, their efficacy in non-high-risk APS patients with isolated venous manifestations is unsolved. Therefore, we performed a sub-group analysis of a previously published meta-analysis after the exclusion of patients with triple positivity and those with history of arterial or small vessel thrombosis. RECENT FINDINGS: We identified 290 APS patients with previous isolated venous event treated with DOACs; among them, 25 (8.6%) patients experienced a recurrent thrombosis in comparison to 16% in the original cohort. We found that the rate of recurrent thrombosis is lower in APS patients with isolated venous manifestations than in overall APS patients including high-risk patients. Research about DOAC use in non-high-risk APS patients needs to be continued.

Vascular Manifestations in Antiphospholipid Syndrome (APS): Is APS a Thrombophilia or a Vasculopathy?

PURPOSE OF REVIEW: Antiphospholipid antibody syndrome (APS) is characterized primarily by thrombosis and pregnancy morbidity. Chronic vascular lesions can also occur. While the underlying mechanisms of these vascular lesions are not entirely known, there have been multiple theories describing the potential process of vasculopathy in APS and the various clinical manifestations associated with it. RECENT FINDINGS: Recently, it has been demonstrated that endothelial proliferation in kidneys can be explained by the activation of the mammalian target of rapamycin complex (mTORC) pathway by antiphospholipid antibodies (aPL). These data support the existence of an APS-related vasculopathy in different locations which can explain-in part-the different manifestations of APS. This review focuses on the various manifestations of APS as a result of APS-related vasculopathy, as well as pathophysiology, current screening, and treatment options for clinicians to be aware of.

Direct Oral Anticoagulants Use in Antiphospholipid Syndrome: Are These Drugs an Effective and Safe Alternative to Warfarin? A Systematic Review of the Literature.

BACKGROUND: The cornerstone of thrombotic antiphospholipid syndrome (APS) patients' management is to prevent recurrent thrombosis by long-term anticoagulation. PURPOSE OF REVIEW: The purpose of the review is to summarize available literature on direct oral anticoagulants (DOACs) use in APS patients through a systematic review and to determine factors associated with thrombosis recurrence. RECENT FINDINGS: The recent RAPS trial demonstrated that APS patients treated with rivaroxaban had a significant twofold-increased thrombin potential, suggesting a higher thrombotic risk, in comparison with warfarin users. Furthermore, several reports of APS patients treated with DOACs have raised safety issues. Our systematic review identified 122 published APS patients treated with DOACs; among them, 19 experienced a recurrent thrombosis while on DOACs. Of note, triple positivity (positivity of all three laboratory criteria for APS) was associated with a 3.5-fold increased risk for recurrent thrombosis. In conclusion, DOACs should be used with caution in APS patients and randomized control trials with clinical primary endpoints assessing clinical efficacy and safety are awaited to establish whether the prescription of DOACs could be a safe alternative to warfarin.