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Atrial fibrillation (AF) prevalence increases in older patients which also show a high thromboembolic risk. Oral anticoagulants (OACs) are recommended to prevent cardioembolic events and direct oral anticoagulants (DOACs) improved anti-thrombotic treatment. However, the benefits/risks of anticoagulant in older patients still need to be completely defined. This retrospective observational study aimed to describe the treatment with OACs in older AF hospitalized patients, and to identify factors influencing OAC therapy or discontinuation using the REgistro Politerapie SIMI. Univariate and multivariate logistic regression models were applied to identify predictors of OACs treatment and discontinuation. Cox proportional hazards models were performed to evaluate one-year mortality by treatment groups. AF patients were 1,128(26.5 %) at discharge and 1,098(97.3 %) required OAC treatment; about half of them (N = 528;48.1 %) were no-OACs users; 236(21.5 %) and 334(30.4 %) used DOACs and VKA, respectively. Increasing DOACs use was observed during the study period. Predictors of OACs treatment were: BMI (OR:1.04; 95 %CI:1.01-1.07), Barthel index (OR:1.01; 95 %CI:1.01-1.02), medications number (OR:1.07; 95 %CI:1.01-1.13). Conversely, a lower probability was found in patients with a high CIR.S (OR:0.59; 95 %CI:0.36-0.97) and neoplasm (OR:0.57; 95 %CI:0.37-0.88). Hospital stay (OR:1.02; 95 %CI:1.01-1.05), neoplasm (OR:2.25; 95 %CI:1.07-4.70) and INR (OR:1.21; 95 %CI:1.05-1.40) increased OACs discontinuation. A lower discontinuation was observed in dyslipidemic patients (OR:0.18; 95 %CI:0.04-0.82) and heart failure (OR:0.38; 95 %CI:0.21-0.70). Among AF patients, 157(14.3 %) died during the follow-up year. Age (HR = 1.05; 95 %CI = 1.03-1.08) and CIR.S (HR = 2.54; 95 %CI = 1.53-4.21) were associated with a greater mortality risk. In conclusion, critical issues related to the underuse and discontinuation of OACs therapy in hospitalized older patients were highlighted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Direct oral anticoagulants (DOACs) reduce stroke risk in patients with device-detected atrial fibrillation (DD-AFib) but increase major bleeding risk. The time to benefit (TTB) and time to harm (TTH) are not well quantified., Objective: The purpose of this study was to determine TTB and TTH in DOAC-treated patients with DD-AFib., Methods: Studies were identified from PubMed searching until November 2023. The primary efficacy outcome was the time to the first stroke event, and the primary safety outcome was the time to the first major bleeding event. Pooled hazard ratio (HR) and its confidence interval (CI) were calculated through reconstructed patient-level data and study-level data. Weibull model and Markov chain Monte Carlo simulation were applied to determine time to specific absolute risk change thresholds., Results: Two trials involving DOACs-NOAH-AFNET 6 (Non-vitamin K antagonist Oral anticoagulants in patients with Atrial High rate episodes) and ARTESiA (Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation)-were identified, which randomized 6548 adults with a mean age of >75 years and a median atrial high-rate episode duration ranging from 1.5 to 2.8 hours. DOACs decreased the risk of stroke (HR 0.67; 95% CI 0.50-0.90) but increased the risk of major bleeding (HR 1.57; 95% CI 1.21-2.04). A TTB of 2.67 years was needed to prevent 1 stroke per 100 DOAC-treated patients, while a TTH of 1.67 years was needed to observe 1 major bleeding., Conclusion: In elderly patients with low durations of DD-AFib, DOACs result in a delayed and restricted stroke-preventive benefit while posing an early-onset bleeding risk. Our findings offer new insights into the risk-benefit profile and provide clinicians an additional dimension to facilitate shared decision-making discussions with patients., Competing Interests: Disclosures Dr Fonarow reports consulting for Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, Johnson & Johnson, Medtronic, Merck, Novartis, and Pfizer. Dr Lip reports a consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi Sankyo, and Anthos with no personal fees. The other authors report no conflict of interest., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Frailty and comorbidity influence the therapeutic approach in everyday clinical practice. The DOACs genericization opens a reflection on their differences from a pharmacological and bioavailability point of view, particularly in elderly frail patients. The aim of this project was to create a national Delphi consensus on the topic of the use of DOACs for atrial fibrillation (AF) in such patients, in light of the genericization of the class., Methods and Results: The consensus dealt with 3 main topics: a) efficacy and safety of DOACs in elderly and/or frail patients; b) therapeutic choice in specific frailty scenarios; c) DOACs genericization. 56 cardiologists, two internists and two neurologists from Italy expressed their level of agreement on each statement by using a 5-point Likert scale (1: strongly disagree, 2: disagree, 3: uncertain, 4: agree, 5: strongly agree). A positive consensus was reached if the percentage of agreement (vote 1-2, positive consensus) or disagreement (votes 4-5, negative consensus) was >66%; otherwise, no consensus was reached. Results are displayed accordingly., Conclusions: After 10 years of everyday clinical management of DOACs for AF, specific elements differentiating a molecule from another, either for efficacy or for safety, are consolidated. However, some uncertainties still exist in particular contexts, such as chronic kidney disease or cancer patients. Clinicians have an unsure attitude towards generic drugs, because clinical practice is lacking as well as a proper knowledge of the topic. Albeit being an alternative, the choice of the generic drug must remain the responsibility of the clinician., Competing Interests: Declaration of competing interest GLB declared speaker fees (small amount) from Bayer Healthcare, Boheringer, Daiichi-Sankyo, Pfizer/BMS, Sanofi. PCa has nothing to declare. PCo participates in Daiichi Sankyo, Inc.-funded research; is a coauthor of ESC guidelines on AF (versions 2010 and 2012) and received institutional research grants from Bayer, Boehringer, and Daiichi Sankyo, Inc.; and speaker honoraria from Bayer, Boehringer Ingelheim, Pfizer-BMS, and Daiichi Sankyo, Inc. In the last two years DMMF has received fees for partecipations as expert in Advisory Boards or as speaker in Congress and meeting or as consultant, from the following companies: Abiogen, Alfasigma, Angelini, Agave, Bayer, Daiichi-Sankyo, Grunenthal, Janssen, Lundbeck, Molteni, Sandoz, SPA, Zambon. ES has nothing to declare. LR is a speaker and a scientific research partner for Bayer, BMS/Pfizer, Boehringer Ingelheim and Daiichi-Sankyo; no fees are directly received personally., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Atrial fibrillation (AF) represents the most common supraventricular arrhythmia, with a prevalence of 1-3 % in the world population. Growing evidences show that AF plays an important role as a risk factor for the development of cognitive impairment (CoI) and dementia, depression and functional limitation. The purpose of the study is to evaluate, in a large cohort of elderly hospitalized patients with nonvalvular AF (NVAF) on direct oral anticoagulants (DOACs) therapy, the prevalence of CoI, depression, and functional limitation, and to assess the different variables that may be detrimental or protective on the risk of CoI or functional limitation. 1004 elderly patients were enrolled, 384 men and 620 women, with a mean age of 84±7.1 years. The two groups were comparable for the main study variables, except for age, prevalence of hypertension and CKD, which were higher in women, while ischemic heart disease was higher in men. In addition, the two groups differed in the CHA 2 DS 2 VASc score 5.3 ± 1.3 vs 4.2 ± 1.4 pts (p < 0.0001) and HAS-BLED score 2.5 ± 0.7 vs 2.3 ± 0.8 pts (p = 0.009) that were significantly higher in women. Our study revealed that in a cohort of elderly patients hospitalized with AF taking DOACs, CoI and disability are widely represented, and female sex increases the risk of being affected by CoI by about 3-fold, while improvement of functional limitations reduce this risk by about 15 %. In addition, CoI and depressive symptoms increase the risk of functional impairment about 2-fold and 28 % respectively, while antihypertensive and anti-diabetic therapy reduce this risk., Competing Interests: Declaration of competing interest The authors declare they have no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Oral anticoagulant therapy (OAT) for managing atrial fibrillation (AF) encompasses vitamin K antagonists (VKAs, such as warfarin), which was the mainstay of anticoagulation therapy before 2010, and direct-acting oral anticoagulants (DOACs, namely dabigatran etexilate, rivaroxaban, apixaban, edoxaban), approved for the prevention of AF stroke over the last thirteen years. Due to the lower risk of major bleeding associated with DOACs, anticoagulant switching is a common practice in AF patients. Nevertheless, there are issues related to OAT switching that still need to be fully understood, especially for patients in whom AF and heart failure (HF) coexist. Herein, the effective impact of the therapeutic switching from warfarin to DOACs in HF patients with AF, in terms of cardiac remodeling, clinical status, endothelial function and inflammatory biomarkers, was assessed by a machine learning (ML) analysis of a clinical database, which ultimately shed light on the real positive and pleiotropic effects mediated by DOACs in addition to their anticoagulant activity.

Introduction: Falls are one of the most fearsome events in anticoagulated older adults. The evidence concerning safety of direct oral anticoagulants (DOACs) in falling elderly patients with atrial fibrillation (AF) is still limited., Methods: We prospectively enrolled consecutive anticoagulant-naïve patients aged 65 years and older, starting anticoagulation with DOACs for AF. The study cohort was stratified in fallers vs. non-fallers, according to the occurrence of at least one fall during the 2-year follow-up and bleeding outcomes were evaluated., Results: We enrolled 524 consecutive patients. Mean age was 80.8 years and they were mostly women (54.0%). Among the study cohort, 148 patients (28.2%) presented at least one fall episode during the study period. After the adjustment for potential confounders, no difference was found between fallers and non-fallers for all the study outcomes: major bleeding [HR: 1.04 (95%CI: 0.58-1.85)], intracranial haemorrhage [HR: 1.63 (95%CI: 0.69-3.80)], clinically relevant non-major bleeding [HR: 1.21 (95%CI: 0.83-1.76)], and all-cause death [HR: 1.51 (95%CI: 0.85-2.69)]. The presence of a prior cerebrovascular event [HR: 2.27 (95%CI: 1.12-4.62); p-value: 0.02] and polypharmacy [HR: 1.60 (95%CI: 1.08-2.39); p-value: 0.02] were the main drivers for major and clinically relevant non-major bleedings, respectively., Conclusions: Falls in an anticoagulant-naïve population aged 65 years and over starting a DOAC for AF do not increase the bleeding risk. Thus, the presence of falls should not discourage clinicians from prescribing DOACs also in this subset of patients., Competing Interests: Declaration of competing interest All the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Although direct oral anticoagulants' (DOACs) prescriptions have experienced immense growth in the last decade, the proportion of discontinuers is still common yielding an increased risk of ischemic stroke (IS) onset., Aims: We aimed to estimate the association between DOACs discontinuation and risk of IS among patients with non-valvular atrial fibrillation (NVAF)., Methods: We used data from a cohort of new DOACs users, followed patients from the first DOAC prescription date up to IS (index date) and conducted a nested case-control analysis using conditional logistic regression. Adjusted odds ratios, 95% confidence intervals were calculated for discontinuation of DOACs (current use compared with past use). The latter, subdivided among those stopping treatment 3 to 2 months and 6 and 3 months prior to index date. The effect of naïve current users against IS onset compared with non-naïve current users was also evaluated., Results: DOACs discontinuation showed an OR of IS of 1.47 (95% CI: 1.02-2.12); estimates were 2.51 (95% CI: 1.84-3.42) for whom discontinued treatment within months 3 and 2 and 1.43 (95% CI: 0.96-2.13) for those between months 6 and 3 prior to index date. Analyzing DOACs individually, risk of IS associated with past users compared with current users: 1.98 (95% CI: 1.25-3.12) for apixaban, 1.38 (95% CI: 0.40-4.72) for edoxaban, 1.98 (95% CI: 1.24-2.65) for dabigatran and 1.87 (95% CI: 1.26-2.76) for rivaroxaban. Similar results were found when stratified by naïve and non-naïve users., Conclusions: DOACs' discontinuation is associated with higher risk of IS, especially in the second and third months following interruption., (© 2023 John Wiley & Sons Ltd.)

Introduction: Direct oral anticoagulants (DOACs) are underused in the elderly, regardless the evidence in their favour in this population., Methods: We prospectively enrolled anticoagulant-naïve patients aged ≥ 75 years who started treatment with DOACs for atrial fibrillation (AF) and stratified them in older adults (aged 75-84 years) and extremely older adults (≥ 85 years). Thrombotic and hemorrhagic events were evaluated for 12 months follow-up., Results: We enrolled 518 consecutive patients. They were mostly aged 75-84 years (299 patients; 57.7%) vs. ≥ 85 years (219 patients; 42.3%). Extremely older adults showed higher incidence of all the endpoints (systemic cardioembolism [HR 3.25 (95% CI 1.71-6.18)], major bleeding [HR 2.75 (95% CI 1.77-4.27)], and clinically relevant non-major bleeding [HR 2.13 (95% CI 1.17-3.92)]) vs. older adults during the first year after starting anticoagulation. In patients aged ≥ 85 years, no difference in the aforementioned endpoints was found between those receiving on-label vs. off-label DOACs. In the extremely older adults, chronic kidney disease, polypharmacy, use of antipsychotics, and DOAC discontinuation correlated with higher rates of thrombotic events, whereas a history of bleeding, Charlson Index ≥ 6, use of reduced DOAC dose, absence of a caregiver, use of non-steroidal anti-inflammatory drugs (NSAIDs), and HAS-BLED score ≥ 3 were associated with major bleedings., Conclusions: Naïve patients aged ≥ 85 who started a DOAC for AF are at higher risk of thrombotic and bleeding events compared to those aged 75-84 years in the first year of therapy. History of bleeding, HAS-BLED score ≥ 3 and use of NSAIDs are associated with higher rates of major bleeding., (© 2023. The Author(s).)

Background: Direct oral anticoagulants (DOACs) are widely used for the treatment of venous thromboembolism (VTE) and for stroke prevention in atrial fibrillation (AF). However, evidence in obese and underweight patients is limited. We assessed the safety and effectiveness of DOACs and vitamin K antagonists (VKAs) in patients  ≥ 120 kg or ≤ 50 kg enrolled in an observational prospective cohort study, the START-Register., Methods: Adult patients started on anticoagulant therapy were followed up for a median of 1.5 years (IQR 0.6-2.8). Primary efficacy outcome was the occurrence of VTE recurrence, stroke and systemic embolism. Primary safety outcome was major bleeding (MB)., Results: 10,080 AF and VTE patients were enrolled between March 2011 and June 2021, 295 patients weighted  ≤ 50 kg and 82 patients ≥ 120 kg. Obese patients were significantly younger than underweight patients. Rates of thrombotic events were low and similar between DOACs and VKAs in underweight patients (1 event on DOACs therapy [0.9% 95% CI 0.11-5.39] and 2 on VKAs [1.1% 95% CI 0.01-47.68]) and in overweight patients (0 events on DOACs, 1 on VKAs [1.6%, 95% CI 0.11-5.79]. Two MB events occurred on DOACs (1.9%, 95% CI 0.38-6.00) and 3 on VKAs (1.6%, 95% CI 0.04-22.06) in the underweight group; 1 MB on DOACs (5.3% 95% CI 0.33-16.68) and 2 on VKAs (3.3%, 95% CI 0.02-130.77) in the overweight group., Conclusions: DOACs seem to be effective and safe also for the treatment of patients with extreme body weights, both underweight and overweight. Further prospective studies are needed to support these findings., (© 2023. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Background: Diabetes represents a pro-thrombotic condition., Objectives: The primary objective was to evaluate the effects of Vitamin K Antagonist (VKA) compared to direct oral anticoagulants (DOACs) in diabetic and nondiabetic patients with non-valvular atrial fibrillation, newly diagnosed. The secondary objective was to evaluate the effects on the risk of bleeding., Methods: We enrolled 300 patients with newly diagnosed atrial fibrillation. One hundred and sixteen patients were taking warfarin, 31 acenocumarol, 22 dabigatran, 80 rivaroxaban, 34 apixaban, and 17 edoxaban. We evaluated: anthropometric parameters, glycated hemoglobin (HbA 1c ), fasting and post-prandial glucose (FPG, and PPG), lipid profile, Lp(a), small and dense low-density lipoprotein (SD-LDL), oxidized LDL (Ox-LDL), I-troponin (I-Tn), creatinine, transaminases, iron, red blood cells (RBC); hemoglobin (Hb), platelets (PLT), fibrinogen, D-dimer, anti-thrombin III, C-reactive protein (Hs-CRP), Metalloproteinases-2 (MMP-2), Metalloproteinases-9 (MMP-9), and incidence of bleeding., Results: We did not record any differences among nondiabetic patients between VKA and DOACs. However, when we considered diabetic patients, we found a slight, but significant improvement of triglycerides and SD-LDL. As regards incidence of bleeding, minor bleeding was more frequent in VKA diabetic group compared to DOACs diabetic group; furthermore, the incidence of major bleeding was higher with VKA in nondiabetic and diabetic group, compared to patients with DOACs. Among DOACs, we recorded a higher incidence of bleeding (minor and major) with dabigatran compared to rivaroxaban, apixaban and edoxaban in nondiabetic and diabetic patients., Conclusion: DOACs seem to be metabolically favourable in diabetic patients. Regarding incidence of bleeding, DOACs with the exception of dabigatran, seem better than VKA in diabetic patients., Competing Interests: Declaration of competing interest The authors' research was supported by IRCCS Policlinico San Matteo Foundation with a grant for “Ricerca Corrente” project. The funding source of this study did not have any role in the study design, or in conducting the practical work of writing the report. The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Altered direct oral anticoagulant (DOAC) plasma levels can lead either to spontaneous hemorrhagic or thrombotic complications. We describe a case of suspected altered apixaban disposition in a patient with an upper gastrointestinal cancer resection treated with apixaban for non-valvular atrial fibrillation. Diagnosis of ischemic stroke for left hemiparesis was confirmed due to recent emergence of a hypodense area in the posterior capsular nucleus of ischemic reference in a context of binuclear capsular lacunar lesions. Thus, apixaban underexposure was suspected from anamnestic data and oral anticoagulation was switched to parenteral at the next scheduled dose for stroke recurrence. Before switching apixaban pharmacokinetic analysis was performed and unexpectedly showed apixaban plasma overexposure. After 3 days from the switch, the patient experienced spontaneous bleeding complications, for which the risk-benefit profile of continuing anticoagulant treatment for stroke recurrences warranted treatment discontinuation. Unexpected DOAC plasma exposure may present in special patient populations with thrombotic and bleeding complications. Though universally recognized therapeutic ranges have yet to be established for DOACs, periodic drug monitoring may aid in guiding optimization of DOAC therapy and reduce the risk of adverse events in special patient populations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Diltiazem is a commonly used medication in patients with atrial fibrillation (AF) with potential for a drug-drug interaction (DDI) with direct oral anticoagulants (DOACs). We aimed to assess the risk of major bleeding after co-prescription of diltiazem and DOACs among adults with AF., Methods: We conducted a population-based, nested case-control study in Ontario, Canada. The study population included all patients with AF > 66 years on a DOAC between April 1, 2011, and March 31, 2018. Cases were patients admitted with major bleeding (index date). Each case was matched to two controls. We categorized exposure to diltiazem before the index date as: (a) current users (diltiazem use within 7 days); (b) recent users (diltiazem use within 8 to 90 days); and (c) unexposed (no diltiazem prescription or diltiazem prescription > 90 days before index date). Conditional logistic regression models were used to examine the association between bleeding and diltiazem co-prescription., Results: Among 86,679 AF patients on a DOAC, the median age of AF patients was 80 years (interquartile range 75-85); 48.3% were women. We identified 2,766 cases (3.2%) who were hospitalized with major bleeding. After multivariable adjustment, there was a significant association between major bleeding and current use of diltiazem (adjusted odds ratio (aOR) 1.37; 95% confidence interval (CI) 1.08-1.73, p < 0.009) but no significant association between major bleeding and recent use of diltiazem (aOR 1.19, 95% CI 0.99-1.42, p = 0.06) as compared with the unexposed group., Conclusions: Current use of diltiazem was associated with major bleeding among AF patients receiving a DOAC., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The administration of an anticoagulant in patients with liver disease (nonalcoholic steatohepatitis-NASH, nonalcoholic fatty liver disease-NAFLD, chronic hepatitis, or cirrhosis) who have an indication (atrial fibrillation, venous thrombosis, or pulmonary embolism) is challenging because there is an imbalance between thrombosis and bleeding. There is a need to focus our attention on preventing risk factors because diabetes, obesity, dyslipidemia, smoking, and sedentary behavior are risk factors for both NASH/NAFLD and AF, and these patients require anticoagulant treatment. Patients with advanced liver disease (Child-Pugh C) were excluded from studies, so vitamin K antagonists (VKAs) are still recommended. Currently, VKAs are recommended for other conditions (antiphospholipid syndrome, mitral valve stenosis, and mechanical valve prosthesis). Amongst the patients under chronic anticoagulant treatment, especially for the elderly, bleeding as a result of the improper use of warfarin is one of the important causes of emergency admissions due to adverse reactions. DOACs are considered to be efficient and safe, with apixaban offering superior protection against stroke and a good safety profile as far as major bleeding is concerned compared to warfarin. DOACs are safe in the Child-Pugh A and B classes (except rivaroxaban), and in the Child-Pugh C class are contraindicated. Given that there are certain and reliable data for chronic kidney disease regarding the recommendations, in liver function impairment more randomized studies must be carried out, as the current data are still uncertain. In particular, DOACs have a simple administration, minimal medication interactions, a high safety and effectiveness profile, and now a reversal agent is available (for dabigatran and idarucizumab). Patients are also statistically more compliant and do not require INR monitoring.

Aims: Left atrial appendage closure (LAAC) has been demonstrated to be cost-saving relative to oral anticoagulants for stroke prophylaxis in patients with non-valvular atrial fibrillation (NVAF) in the United States and Europe. This study assessed the cost-effectiveness of LAAC with the Watchman device relative to warfarin and direct oral anticoagulants (DOACs) for stroke risk reduction in NVAF from a Japanese public healthcare payer perspective., Methods: A Markov model was developed with 70-year-old patients using a lifetime time horizon. LAAC clinical inputs were from pooled, 5-year PROTECT AF and PREVAIL trials; warfarin and DOAC inputs were from published meta-analyses. Baseline stroke and bleeding risks were from the SALUTE trial on LAAC. Cost inputs were from the Japanese Medical Data Vision database. Probabilistic and one-way sensitivity analyses were performed., Results: Over the lifetime time horizon, LAAC was less costly than warfarin (savings of JPY 1,878,335, equivalent to US $17,600) and DOACs (savings of JPY 1,198,096, equivalent to US $11,226). LAAC also provided 1.500 more incremental quality-adjusted life years (QALYs) than warfarin and 0.996 more than DOACs. In probabilistic sensitivity analysis, LAAC was cost-effective relative to warfarin and DOACs in 99.98% and 99.73% of simulations, respectively. LAAC dominated (had higher cumulative QALYs and was less costly than) warfarin and DOACs in 89.94% and 83.35% of simulations, respectively., Conclusions: Over a lifetime time horizon, LAAC is cost-saving relative to warfarin and DOACs for stroke risk reduction in NVAF patients in Japan and is associated with improved quality-of-life.

Background: Direct oral anticoagulants (DOACs) are frequently prescribed for the management of atrial fibrillation and venous thrombosis. There is a lack of published data on the utilization of DOACs in individuals who have undergone recent cardiac surgery. The purpose of this study was to evaluate the safety and efficacy of apixaban and rivaroxaban compared to warfarin in patients postcardiac surgery., Methods: In this retrospective cohort study, patients were separated into a DOAC cohort or a warfarin cohort based on the agent they received after cardiac surgery. Patients could be included if they were ≥18 years of age and received or were discharged on either rivaroxaban, apixaban, or warfarin within 7 days after cardiac surgery. The primary outcome for the study was the rate of International Society on Thrombosis and Hemostasis (ISTH) major bleeding during hospitalization and for 30 days following discharge or until first follow-up appointment., Results: There were a total of 194 patients included in the analysis, 97 in the DOAC cohort and 97 in the warfarin cohort. Four patients (4.1%) in the DOAC group experienced ISTH major bleeding, while 2 patients (2.1%) in the warfarin cohort experienced ISTH major bleeding (p = 0.68). No patients in the DOAC cohort experienced a thrombotic event, whereas 2 patients (2.1%) in the warfarin cohort experienced a thrombotic complication (p = 0.5)., Conclusion: Apixaban and rivaroxaban demonstrated similar safety when compared to a matched cohort of warfarin patients. Larger prospective randomized studies are needed to confirm these findings., (© 2022 The Authors. Journal of Cardiac Surgery published by Wiley Periodicals LLC.)

Non-vitamin K antagonist oral anticoagulants (NOACs) have revolutionized treatment of atrial fibrillation. Although benefits of anticoagulation therapy are clear, a minority of patients still experience treatment inefficacy or harm. All NOACs have varying degree of renal clearance, which may significantly affect plasma concentrations. Pivotal clinical trials have explored the effects of dose reduction in patients with chronic renal disease. None of these have, however, specifically addressed the need for a dose up-titration in patients with renal hyperfiltration, in whom lower drug plasma levels are to be expected. A signal for lower efficacy in this patient subset has recently emerged. We systematically assessed the peer-reviewed scientific literature on this topic, including a recently reported randomized pharmacokinetic study in renal hyperfiltrators also reporting on ischemic and bleeding events. We conclude that the reduction in NOAC plasma levels in AF patients with renal hyperfiltration is limited in extent and, does not translate into a clinically meaningful reduction in efficacy for NOACs as compared to vitamin K antagonists (VKAs) in such patients. At the current state of knowledge, NOAC current dosing should not be altered in patients with high-normal renal function., Competing Interests: Declaration of Competing Interest AH: no disclosures. CZ: no disclosures. RPG declares the following: Institutional research grant to the TIMI Study Group at Brigham and Women's Hospital from Anthos and Daiichi Sankyo; Honoraria for Lecture / CME programs from Daiichi Sankyo, Medical Education Resources, Menarini, Merck, Pfizer, SAJA, Servier, Shanghai Medical Telescope; Consultant fees from AstraZeneca, CryoLife, Daiichi Sankyo, Hengrui, Janssen, Pfizer, and Samsung. Dr. Giugliano is a member of the TIMI Study Group which has received institutional research grant support through Brigham and Women's Hospital from AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., Merck, Novartis, Pfizer, The Medicines Company. RDC reports grants from Boehringer Ingelheim, Bayer, BMS/Pfizer Alliance, Daiichi-Sankyo, Menarini, Roche, Novartis, Sanofi, Merck, Portola, AstraZeneca, Amgen and Guidotti, all outside the submitted work., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: Elderly atrial fibrillation (AF) patients with risk factors of bleeding are often considered ineligible for standard oral anticoagulants (OACs). The Edoxaban Low-Dose for EldeR CARE AF patients (ELDERCARE-AF) trial recently showed that edoxaban 15 mg/day was superior to placebo for preventing stroke or systemic embolism and did not result in a significantly higher incidence of major bleeding. Our aim was to investigate a real-world cohort of AF patients similar to the ELDERCARE-AF cohort, with regard to the impact of direct oral anticoagulant (DOAC) use compared to non-OAC use, in relation to clinical outcomes., Methods and Results: From 1 January 2012 to 31 December 2016, 15 183 AF patients aged ≥80 years (mean age 86.63 years [SD 4.79]; 48.7% male) with a congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and prior stroke or transient ischemic attack (CHADS2) score ≥2 who met the enrolment criteria (generally similar to ELDERCARE-AF) were identified from the Taiwan National Health Insurance Research Database. Patients were categorized into two groups according to their stroke prevention strategies, i.e. without OACs (n = 9084) and DOACs (n = 6099). Patients receiving DOACs were further stratified into reduced-dose- or full-dose-regimen groups. Compared with the non-OAC group as a reference, DOAC use (whether at reduced dose or full dose) was associated with a lower risk of ischaemic stroke (adjusted hazard ratio [aHR] 0.77, 95% confidence interval [CI] 0.67-0.88) and all-cause mortality (aHR 0.39, 95% CI 0.37-0.42), while the risks of intracranial haemorrhage and major bleeding were similar. The risks of composite outcomes of 'ischaemic stroke or mortality' (aHR 0.42, 95% CI 0.40-0.45) and 'ischaemic stroke or major bleeding or mortality' (aHR 0.49, 95% CI 0.46-0.52) were significantly lower with DOAC use. When compared with the non-OAC group as the reference group, DOACs (whether reduced dose or full dose) showed a positive net clinical benefit. The results were generally consistent even after propensity matching., Conclusion: In routine clinical care, DOACs (whether reduced or full dose) were associated with a lower risk of ischaemic stroke, mortality, and the composite endpoint, when compared with non-OAC use in high-risk elderly AF patients at increased bleeding risk. Our findings provide complementary 'real-world' data to support the generalizability of the results of the ELDERCARE-AF trial to other DOACs in daily clinical practice., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

In the past decade, direct oral anticoagulants (DOACs) have proven to be the best option for patients with nonvalvular atrial fibrillation. Nevertheless, evidence for the use of DOACs for anticoagulation in valvular atrial fibrillation, particularly after aortic valve replacement, remains inadequate. Thus, we conducted a meta-analysis to compare the efficacy and safety of vitamin K antagonists (VKAs) and DOACs in patients with atrial fibrillation after transcatheter aortic valve replacement (TAVR). We conducted a comprehensive search of online databases, and 11 studies were included in the final analysis. The primary endpoint was all-cause mortality. Secondary endpoints included stroke and cardiovascular death. The safe endpoint is major and/or life-threatening bleeding. Subgroup analysis was conducted according to the different follow-up time of each study. Random-effects models were used for all outcomes. Statistical heterogeneity was assessed using χ 2 tests and quantified using I 2  statistics. Patients in the DOACs group had a significantly lower risk of all-cause mortality compared with patients in the VKAs group (relative risk [RR]: 1.20, 95% confidence interval [CI]: 1.01-1.43, p = .04). This benefit may be greater with longer follow-up. In a subgroup analysis based on the length of follow-up, a significantly lower risk of all-cause mortality was found in the DOACs group in the subgroup with a follow-up time of >12 months (RR: 1.50, 95% CI: 1.07-2.09, p = .001). There were no significant differences between the two groups in cardiovascular death, stroke, and major and/or life-threatening bleeding. For patients with atrial fibrillation after TAVR, the use of DOACs may be superior to VKAs, and the benefit may be greater with longer follow-up. The anticoagulant strategy for atrial fibrillation after TAVR is a valuable direction for future research., (© 2022 The Authors. Clinical Cardiology published by Wiley Periodicals, LLC.)

Objective: People with serious mental illnesses (SMI) have an increased risk of stroke compared to the general population. This study aims to evaluate oral anticoagulation prescription trends in atrial fibrillation (AF) patients with and without a comorbid SMI., Methods: An open-source retrieval system for clinical data (CogStack) was used to identify a cohort of AF patients with SMI who ever had an inpatient admission to King's College Hospital from 2011 to 2020. A Natural Language Processing pipeline was used to calculate CHA2DS2-VASc and HASBLED risk scores from Electronic Health Records free text. Antithrombotic prescriptions of warfarin and Direct acting oral anti-coagulants (DOACs) (apixaban, rivaroxaban, dabigatran, edoxaban) were extracted from discharge summaries., Results: Among patients included in the study (n = 16 916), 2.7% had a recorded co-morbid SMI diagnosis. Compared to non-SMI patients, those with SMI had significantly higher CHA2DS2-VASc (mean (SD): 5.3 (1.96) vs 4.7 (2.08), p < 0.001) and HASBLED scores (mean (SD): 3.2 (1.27) vs 2.5 (1.29), p < 0.001). Among AF patients having a CHA2DS2-VASc ≥2, those with co-morbid SMI were less likely than non-SMI patients to be prescribed an OAC (44% vs 54%, p < 0.001). However, there was no evidence of a significant difference between the two groups since 2019., Conclusion: Over recent years, DOAC prescription rates have increased among AF patients with SMI in acute hospitals. More research is needed to confirm whether the introduction of DOACs has reduced OAC treatment gaps in people with serious mental illness and to assess whether the use of DOACs has improved health outcomes in this population., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The most frequent arrhythmia treated is atrial fibrillation (AF), which necessitates the use of oral anticoagulants (OACs) to reduce the risk of thromboembolism and stroke. Patients with chronic kidney disease are more likely to develop AF, with a 10% frequency among those on chronic dialysis. Warfarin is the most widely prescribed OAC for individuals with end-stage kidney disease (ESKD). On the other hand, direct OACs (DOACs) are generally safer than warfarin, with fewer fatal bleeding events and a fixed dose that does not require close international normalized ratio (INR) monitoring. For those patients, warfarin and apixaban appear to be FDA-approved, whereas dabigatran, rivaroxaban, and edoxaban are not recommended yet. Due to a lack of large randomized studies, data from major trials cannot be extended to dialysis patients. In this review, we summarize the available data and literature referring to patients on chronic hemodialysis with concomitant AF. Due to the scarcity of data, we try to assist clinicians in selecting the appropriate therapy according to the specific characteristics of each patient. Finally, future directions are provided in two key areas of focus: left atrial appendage closure therapies and genetic research., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s). Published by IMR Press.)

Purpose of Review: Direct oral anticoagulants (DOACs) are increasingly used for the treatment and prevention of thromboembolic events in patients with non-valvular atrial fibrillation (AF). Evidence regarding their role in patients with AF and concurrent valvular heart disease (VHD) continues to evolve., Recent Findings: Post hoc analyses of randomized clinical trials suggest that DOACs are non-inferior to warfarin for the prevention of stroke or systemic embolism in patients with AF and VHD. Emerging evidence from observational data showed a favorable benefit-risk profile for DOACs compared to warfarin in patients with AF and VHD. DOACs are an attractive option for the treatment of patients with AF and VHD who cannot tolerate or have contraindications to warfarin therapy. Future studies are needed to evaluate their effectiveness, safety, and examine variability in the direction and magnitude of treatment effects in selected VHD subgroups., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: In the treatment of atrial fibrillation (AF), anticoagulant medications such as warfarin and rivaroxaban are commonly prescribed to reduce the risk of ischaemic strokes, and other thromboembolic events. Research has highlighted advantages and disadvantages of each of these medications, but there remains an absence of qualitative evidence regarding the lived experiences of AF patients. The present study helps address this gap and obtain a greater understanding of the patient experience and beliefs surrounding their anticoagulant medication., Method: Semi-structured qualitative interviews with a purposive sample of 20 participants (10 warfarin, 10 rivaroxaban). Interviews were transcribed verbatim and thematically analysed., Results: Data analysis led to the generation of three key themes: positive perceptions of medication, distrust of alternatives, and inconsistencies in support experiences., Conclusions: Positive perceptions of one anticoagulant medication (ACM) and distrust of alternatives may influence patients' confidence in switching medications. This is potentially problematic where there is a lack of patient engagement in medication changes, as seen during the COVID pandemic. Gaps in patient understanding of anticoagulation, including lack of clarity around medications selection and misconceptions about treatment, were evident. By addressing these misconceptions, clinicians may be better positioned to support people with AF in self-management of their ACM., (© 2021 John Wiley & Sons Ltd.)

Background and Aims: Unfractionated-heparin (UFH) is the first-choice parenteral anticoagulant during invasive percutaneous procedures and its effect is monitored by the activated coagulation time (ACT). The effects of the non-vitamin K antagonist oral anticoagulants (NOACs) on the ACT and on ACT prolongation by UFH were not clearly established. We assessed the ACT prolongation induced by different UFH concentrations in blood samples of patients taking the four types of currently marketed NOACs and in patients not taking anticoagulants., Methods and Results: We measured the ACT in patients on dabigatran 110 mg (n = 8), rivaroxaban (n = 10), apixaban (n = 9) and edoxaban (n = 10) at supposed peak plasma concentrations, before and after in vitro addition of 3 UFH concentrations, corresponding to doses of 2000, 5000 and 10,000 IU. Seven non-anticoagulated patients served as controls. Patients in the 5 groups did not differ significantly for age, body weight and glomerular filtration rate. Baseline ACTs (s, mean ± SD) were 192 ± 27, 124 ± 14, 132 ± 14, 151 ± 30 and 134 ± 7 in dabigatran 110, rivaroxaban, apixaban, edoxaban and controls, respectively (P < 0.05 for dabigatran vs the other NOACs). We found a linear prolongation of the ACT with the in vitro UFH addition (P < 0.001), but prolongation was similar between the NOACs and controls., Conclusions: Dabigatran induces a moderate, significant ACT prolongation. None of the NOACs affects the UFH-induced ACT prolongation in the commonly used UFH range. The dose of UFH currently recommended to achieve the target ACT should thus be used irrespective of whether patients are taking NOACs or not., (Copyright © 2022. Published by Elsevier Inc.)

Aims: To clarify the real-world clinical status and prognosis of elderly and very elderly non-valvular atrial fibrillation (NVAF) patients, more than 30 000 elderly patients with NVAF aged ≥75 years were enrolled in the ANAFIE Registry., Methods and Results: This multicentre, prospective, observational study followed elderly NVAF patients in Japan for ∼2 years. Among 32 275 patients (mean age, 81.5 years; men, 57.3%; mean CHA2DS2-VASc score, 4.5), 2445 (7.6%) were not receiving oral anticoagulants (OACs) and 29 830 (92.4%) were given OACs. Of these, 21 585 (66.9%) were receiving direct OACs (DOACs) and 8233 (25.5%), warfarin (mean time in therapeutic range: ∼75%). In total, the 2-year incidence rate was 3.01% for stroke/systemic embolic events (SEE); 2.00%, major bleeding; and 6.95%, all-cause death. When compared with the warfarin group, the DOAC group had a lower hazard ratio (HR) for stroke/SEE, major bleeding, and all-cause death after adjusting for confounders. The group without OACs had a higher HR for stroke/SEE and all-cause death, with a lower HR for major bleeding. History of falls within 1 year at enrolment and of catheter ablation were positive and negative independent risk factors, respectively, for stroke/SEE, major bleeding, and all-cause death., Conclusion: In Japan, a large proportion of elderly and very elderly NVAF patients were receiving DOACs, which was significantly associated with lower rates of stroke/SEE, major bleeding, and all-cause death vs. well-controlled warfarin. History of falls and of catheter ablation were independently associated with stroke/SEE, major bleeding, and all-cause death., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: We assessed switching patterns of oral anticoagulants (OACs) in patients with atrial fibrillation (AF) in the period following widespread availability of the direct-acting oral anticoagulants (DOACs)., Research Design and Methods: A retrospective cohort study was conducted using NPS MedicineWise's MedicineInsight dataset, collected from Australian general practices. Patients with AF who newly commenced an OAC between 1 January 2013 and 30 September 2017 were included. The switching rate was calculated within 12 months post-initiation. Switching rates between OACs were compared, and predictors of switching were identified., Results: We included 15,020 patients who were recorded as having been commenced on warfarin or a DOAC. Overall, 5.7% of patients switched their OAC within 12 months. The switching rates from warfarin, apixaban, dabigatran and rivaroxaban were 9.4%, 2.6%, 8.9% and 4.0%, respectively. Compared to apixaban, commencement on warfarin, dabigatran or rivaroxaban was associated with a higher risk of switching to another OAC. Patients with an estimated glomerular filtration rate (eGFR) <30 mL/min were more likely to switch from DOACs to warfarin and less likely to switch from warfarin, compared to those with an eGFR >60 mL/min., Conclusion: There was a low switching rate between OACs in Australian general practice patients with AF. A key determinant of switching appeared to be kidney disease.

In the past decade, direct oral anticoagulants (DOACs) have transformed the world of anti-thrombotic therapy. Edoxaban is the most recently approved DOAC. Though intended for use primarily in stroke prevention, it has found applications in various other conditions including thromboembolic and peripheral arterial disease. This review aims to provide a detailed outline of the growing indications, evidence for use in special populations, pharmacogenetics and side-effect profile of edoxaban., (© 2021 British Pharmacological Society.)

Heart failure (HF) is characterized by a pro-thrombotic state, which might aggravate its morbidity and, consequently, mortality. Several and commonly observed comorbidities, such as coronary artery disease, atrial fibrillation (AF), renal dysfunction, and diabetes often complicate HF, increasing the thromboembolic risk. In the past decade, direct oral anticoagulants (DOACs) have been approved for the treatment and prevention of stroke and embolic events in patients with nonvalvular AF. Due to their lower bleeding risk, these drugs are frequently used instead of warfarin; however, some controversies exist on their use in HF patients with or without comorbidities. Indeed, the management of anticoagulation in HF patients with underlying conditions is poorly investigated since these patients are underrepresented or excluded from randomized controlled trials. The aim of this research is to review current evidence on the use of DOACs in HF patients, also discussing their specific use in different clinical scenarios. Graphical abstract., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Atrial fibrillation (AF) increases the risk of developing a stroke by 20%. AF related strokes are associated with greater morbidity. Historically, warfarin was the anticoagulant of choice for stroke prevention in patients with AF but lately patients are being switched or started on direct oral anticoagulants (DOACs). DOACs are promoted as safer alternatives to warfarin and it is expected that they will be associated with fewer challenges both for patients and healthcare professionals. This systematic narrative review aimed to explore perspectives of patients and professionals on medicines optimisation of oral anticoagulation with vitamin K antagonists and DOACs in atrial fibrillation., Methods: Prospero registration CRD42018091591. Systematic searches undertaken of research studies (qualitative and quantitative), published February 2018 to November 2020 from several databases (Web of Science, Scopus, Medline Via Ovid, CINHAL via Ebsco, and PubMED via NCBI) following PRISMA methodology. Data were organised using Covidence software. Two reviewers independently assessed the quality of the included studies and synthesized the findings (thematic analysis approach)., Results: Thirty-four studies were included. Studies were critically appraised using established critical appraisal tools (Qualsyst) and a risk of bias was assigned. Clinicians considered old age and the associated complexities such as co-morbidities and the increased potential for bleeding as potential barriers to optimising anticoagulation. Whereas patients' health and medication beliefs influenced adherence. Notably, structured patient support was important in enhancing safety and effective anticoagulation. For both patients and clinicians, confidence and experience of safe anticoagulation was influenced by the presence of co-morbidities,  poor knowledge and understanding of AF and the purpose of anticoagulation., Conclusion: Age, complex multimorbidity and polypharmacy influence prescribing, with DOACs being perceived to be safer than warfarin. This systematic narrative review suggests that interventions are needed to support patient self-management. There are residual anxieties associated with long term anticoagulation in the context of complexities., Trial Registration: Not applicable., (© 2021. The Author(s).)

Objective: The aim of this study was to investigate the association between oral anticoagulant type (direct oral anticoagulants (DOACs) vs vitamin K antagonists (VKAs)) and incident dementia or mild cognitive impairment (MCI) among patients with newly diagnosed atrial fibrillation (AF)., Methods: Using linked electronic health record (EHR) data from the Clinical Practice Research Datalink in the UK, we conducted a historical cohort study among first-time oral anticoagulant users with incident non-valvular AF diagnosed from 2012 to 2018. We compared the incidence of (1) clinically coded dementia and (2) MCI between patients prescribed VKAs and DOACs using Cox proportional hazards regression models, with age as the underlying timescale, accounting for calendar time and time on treatment, sociodemographic and lifestyle factors, clinical comorbidities and medications., Results: Of 39 200 first-time oral anticoagulant users (44.6% female, median age 76 years, IQR 68-83), 20 687 (53%) were prescribed a VKA and 18 513 (47%) a DOAC at baseline. Overall, 1258 patients (3.2%) had GP-recorded incident dementia, incidence rate 16.5 per 1000 person-years. DOAC treatment for AF was associated with a 16% reduction in dementia diagnosis compared with VKA treatment in the whole cohort (adjusted HR 0.84, 95% CI: 0.73 to 0.98) and with a 26% reduction in incident MCI (adjusted HR 0.74, 95% CI: 0.65 to 0.84). Findings were similar across various sensitivity analyses., Conclusions: Incident EHR-recorded dementia and MCI were less common among patients prescribed DOACs for new AF compared with those prescribed VKAs., Competing Interests: Competing interests: LS reports grants from Wellcome, Medical Research Council, National Institute of Health Research, Glaxo Smith Kline, the British Heart Foundation and Diabetes UK, outside the submitted work and is a Trustee of the British Heart Foundation. CW-G reports grants from Wellcome, during the conduct of the study and grants from British Heart Foundation and the Alzeinher’s Society, outside the submitted work. SLC, EP, AYW and KW have nothing to disclose., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Purpose: Direct oral anticoagulants (DOACs) are recommended in preference to vitamin K antagonists (VKAs) for stroke prevention in patients with atrial fibrillation (AF) eligible for oral anticoagulation therapy; however, data and clinical experiences supporting the use of DOACs in patients with a body mass index ≥40 kg/m 2 or weight >120 kg remain limited. The aim of this study was to evaluate the pharmacokinetic properties of DOACs in patients with AF and extreme obesity., Methods: We enrolled all consecutive patients with AF and extreme obesity undergoing treatment with DOACs followed up at Monaldi Hospital, Naples, Italy. To determine peak plasma and trough levels of DOACs, plasma samples were collected at 2nd, 4th, 6th, and 12th hours from the last dose intake in patients receiving apixaban and dabigatran and at the 2nd, 4th, 6th, and 24th hours in those receiving edoxaban and rivaroxaban. The DOACs' peak and trough plasma levels obtained from our study population were compared with those sourced from pharmacokinetic studies among patients without obesity, defined as a normal reference range in the literature. If at least 1 peak or trough plasma level was found ​​below or above the normal reference ranges, the patients were classified as having out-of-range DOAC plasma levels. Study population was then divided into in-range and out-of-range groups. Baseline characteristics, including DOAC treatment, were compared between the 2 groups. Univariate and multivariate logistic regression analysis were performed to identify baseline variables associated with DOACs' plasma concentration out of the expected range., Findings: A total of 58 patients (mean [SD] age, 70.93 [8.73] years; 40% female) with extreme obesity (mean [SD] body mass index. 44.43 [3.54] kg/m 2 ) and AF while undergoing DOAC treatment were included in the present study. In 9 patients (15.5 %), the DOAC plasma concentrations were out of the expected ranges (out-of-range group);, indicating a greater likelihood of edoxaban 30 mg treatment (33% vs 2%; P < 0.01) and inappropriate DOAC underdosing (56% vs 4%; P < 0.005) compared with the in-range group. According to the multivariate logistic analysis (P = 0.0011), the inappropriate DOAC underdosing (hazard ratio = 29.37; P = 0.0002) was an independent predictor of DOAC plasma levels out of the expected ranges., Implications: Patients with extreme obesity and AF who were receiving DOAC therapy had DOAC plasma concentrations in the expected range. The inappropriate DOAC underdosing seems to be the only independent clinical factor associated with a plasma concentration of the drug out of the expected range., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: To systematically review available evidence of indirect comparisons from RCTs and direct comparisons from observational studies regarding the comparative effectiveness and safety of DOACs in patients with AF., Methods: Electronic databases including EMBASE, MEDLINE, and PUBMED were searched up to June 5th, 2020. Primary endpoints included effectiveness (stroke or systemic embolism [SE]) and safety (major bleeding) outcomes. Bucher methods and random-effects models were conducted for indirect and direct comparisons among DOACs, respectively. Ranking probability analyses and the number needed to treat for net effect (NNTnet) were applied., Results: A total of 36 studies, involving 7 RCTs (n = 60,292 patients) and 29 observational studies (n = 1,164,821 patients), were included for analyses. Regarding the risk of stroke/SE, no significant differences were found from indirect comparisons of RCTs among the DOACs. For major bleeding, apixaban tended to be safer than rivaroxaban and dabigatran based on both direct and indirect comparisons (all p < 0.05; evidence quality: very low to moderate). Ranking probability analysis showed that apixaban had a high probability of being the best treatment in decreased risk of stroke/SE and major bleeding (80.30% and 91.30%, respectively). Likewise, apixaban was found to have the highest net clinical benefit (0.02, 95% CI: 0.014-0.029) and smallest NNTnet (48, 95% CI: 35-74)., Conclusions: Apixaban appeared to have a favorable effectiveness-safety profile compared with the other DOACs in AF for stroke prevention, based on evidence from both direct and indirect comparisons. However, additional high-quality evidence is needed to support firm recommendations on clinical decision-making., (© 2021. Springer Nature B.V.)

Atrial fibrillation and diabetes: time to reconsider duration of the disease to evaluate the bleeding risk? Impact of diabetes status in patients suffering of non-valvular atrial fibrillation requiring anticoagulation have been analysed previously and risk/benefit balance of NOACs have been confirmed in these patients. The implication of that pathology in the evaluation of the thrombotic risk is discussed but more importantly bleeding risk in this growing population is analysed, perhaps neglected until now.

Background: Direct oral anticoagulants (DOACs) have been proven to be effective and safe for prevention of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). However, suboptimal adherence, variable dosing and use in patient populations that otherwise would have been excluded from clinical trials may impact the efficacy and safety profile of DOACs in a routine care setting. We compared stroke, bleeding, and mortality rates on and off therapy for standard and low-dose DOACs (apixaban, rivaroxaban, dabigatran) versus warfarin in a Canadian cohort. We also assessed persistence of DOACs compared to warfarin., Methods: We conducted six 1-1 propensity-score matched retrospective cohort analyses using Quebec health administrative databases (2011-2017). NVAF patients (≥18 years) covered by the public medication insurance plan entered the cohort on the first OAC dispensation date. We excluded those with OAC use in the previous year or stroke or bleeding diagnoses in the previous two years. Follow-up ended at death, March 2017 or end of medication coverage by the public plan. Time-dependent Cox regression was applied., Results: We evaluated 10,893 patients initiated on apixaban (7206 standard, 3687 low-dose), 10,190 on rivaroxaban (7396 standard, 2794 low-dose), 5884 on dabigatran (2756 standard, 3128 low-dose), and propensity score-matched warfarin users. Across standard-dose DOACs, compared to warfarin, stroke risks were similar; bleeding risks were lower with apixaban (hazard ratio 0.63; 95% confidence interval 0.52-0.77) and dabigatran (0.47; 0.35-0.64) but not rivaroxaban (0.93; 0.79-1.10); death risks were lower with all DOACs. For low-dose DOACs, rivaroxaban demonstrated higher stroke (1.79; 1.21-2.64) and bleeding risks (1.37; 1.09-1.73); other agents had stroke risks similar to warfarin and bleeding risks lower than warfarin; only low-dose dabigatran had lower death risk (0.59; 0.52-0.68). Treatment discontinuation was lower with DOACs versus warfarin with the exception of low-dose rivaroxaban. The risks of stroke were 2-4 folds higher during time off any OAC versus time on warfarin. The risks of death were higher, while the risks of bleeding were generally lower during times off any OAC., Conclusions: Standard-dose DOACs had similar stroke, better persistence and mortality profiles than warfarin. Only standard dose apixaban and dabigatran had better bleeding profiles than warfarin. Low-dose rivaroxaban had worse persistence, stroke and bleeding profiles than warfarin, while low-dose apixaban and dabigatran had similar stroke and better bleeding profiles. Real-world use of DOACs may explain some of the differences observed in Canadian routine care versus the phase III clinical trials., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Patient's adherence to oral anticoagulant therapy is essential to prevent and treat thrombotic events., Methods: To assess the patients' adherence Morisky Medication Adherence Scale 8-items was used. The target population included 785 consecutive outpatients, of whom 384 were on Vitamin K Antagonists and 401 on Direct Oral Anticoagulants. Moreover, we evaluate which variable among age, gender, having experienced a thrombotic episode, time in the therapeutic range for patients on Vitamin K Antagonists, being naive and once versus twice daily drug assumption for patients on Direct Oral Anticoagulants, could affect adherence to therapy., Results: Morisky Medication Adherence Scale 8-items score was 8 in both groups. The intentional non-adherence obtained the lowest score while the unintentional non-adherence is the most frequent problem in patients treated with either Vitamin K Antagonists or Direct Oral Anticoagulants. Age > 75 years, male gender, having experienced a thrombotic episode, being naive and assuming Direct Oral Anticoagulants twice a day were significantly associated with a higher risk to forget assuming the oral anticoagulant, to have more difficulty in remembering to take it or to bring it in case of travel or leaving home. A low percentage of time in therapeutic range was associated with a not regularly assumption of the anticoagulants., Conclusion: Patients treated with Vitamin K Antagonists or Direct Oral Anticoagulants show a good adherence and persistence to their oral anticoagulant therapy. Several factors have been identified to affect patients' adherence and deserve a careful attention by the doctors at the Anticoagulation Clinic., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Objectives: After the Fontan procedure, thromboembolic events need to be prevented. We present a young patient with a history of Fontan procedure and poor adherence to warfarin who developed systemic thromboembolism. He was changed to maintenance dabigatran, which is one of the available direct oral anticoagulants (DOACs). Case presentation: A 20-year-old man was diagnosed with cerebral infarct, pulmonary thromboembolism (PTE), and renal infarcts. He was prescribed warfarin to prevent thromboembolic events after the Fontan procedure. Based on his poor adherence to warfarin, we decided to change the anticoagulant therapy from warfarin to dabigatran 150 mg bid. One month later, his pulmonary thromboembolism regressed. Conclusion: Our case report showed a young adult with low compliance to warfarin who developed cerebral, pulmonary, and renal thromboembolic events. Thus, in our opinion, the change from warfarin to a DOAC was necessary for further prevention and treatment of PTE. A change from warfarin to a DOAC should be considered in patients with poor compliance who are at high risk of thromboembolic events, for example, after the Fontan procedure.

Cancer patients are at an increased risk of developing atrial fibrillation (AF) and thrombosis. However, the management of anticoagulation in patients with both diseases may be challenging, and data on these patients are lacking. We summarize the current evidence on the incidence and prevalence of cancer in AF and vice versa and provide some practical considerations on the management of oral anticoagulation in specific clinical situations. Low-molecular weight heparins are not approved for thromboprophylaxis in AF, and management of warfarin can be difficult. The use of direct oral anticoagulants may be particularly attractive for their rapid onset/offset action and lower bleeding risk., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: To analyse the safety and efficacy of direct oral anticoagulants (DOACs) in real-world studies including atrial fibrillation (AF) patients., Methods and Results: Systematic review and meta-analysis of observational studies including AF patients on DOACs. Primary endpoints: any, major, gastrointestinal (GI), intracranial haemorrhage (ICH), and haemorrhagic stroke (HS). Secondary endpoints: ischaemic stroke (IS), systemic embolism (SE), myocardial infarction (MI), and all-cause of death. A set of pair-wise meta-analyses using a random effect model and a random effect network meta-analysis under a Bayesian framework were performed. Prospero registration number: CRD42019137111. We included 21 studies with 605 771 AF patients. Apixaban was associated with lower major and GI bleeding compared with Rivaroxaban [hazard ratio (HR) 2.0, 95% confidence interval (CI) 1.6-2.5] and Dabigatran (HR 1.6, 95% CI 1.3-2.1). The latter drug performed better than Rivaroxaban (HR 1.2, 95% CI 1.0-1.5). Dabigatran and Apixaban had a similar association with HS, but Apixaban performed better than Rivaroxaban (HR 1.8, 95% CI 1.1-3.0). Apixaban had a similar association with Rivaroxaban and Dabigatran for ICH, the latter drug performing better than Rivaroxaban (HR 1.3, 95% CI 1.0-1.7). Rankograms showed that Apixaban was likely to be the first-choice treatment in relation to any (65%) major (100%) and GI bleeding (100%) followed by Dabigatran (46%, 100%, 99%, respectively). Dabigatran and Apixaban had similar rank as first choice for ICH (44% and 55%) and HS (52% and 48%). DOACs showed similar association with IS/SE, MI, all-cause of death., Conclusions: Analysis of real-world studies shows significant differences for safety among DOACs., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: Direct oral anticoagulants (DOACs) are recommended for stroke prevention in patients with atrial fibrillation (AF) or for treatment of deep vein thrombosis, although some concerns about safety and efficacy were raised on the use of these drugs in patients with advanced liver disease (ALD). We want to investigate the association of DOACs use with the bleeding and ischaemic risk., Material and Methods: We performed a systematic review and metanalysis of clinical studies retrieved from PubMed (via MEDLINE) and Cochrane (CENTRAL) databases addressing the impact of DOACs therapy on bleeding events including intracranial haemorrhage (ICH), gastrointestinal and major bleeding. Secondary end points were all-cause death, ischaemic stroke/systemic embolism (IS/SE) and recurrence/progression of vein thrombosis (rDVT)., Results: 12 studies were included in the meta-analysis: a total of 43 532 patients with ALD or cirrhosis, of whom 27 574 (63.3%) were on treatment with DOACs and 15 958 were in warfarin/low molecular weight heparin. DOACs reduced the incidence of major bleeding by 61% (pooled Hazard Ratio [HR] 0.39, 95% Confidence Interval [CI] 0.21-0.70), ICH by 52% (HR 0.48, 95% CI 0.40-0.59), while no difference in the reduction of any and gastrointestinal bleeding were observed. DOACs reduced also rDVT by 82% (HR 0.18, 95%CI 0.06-0.57), but did not reduce death and IS/SE. No difference was shown according to oesophageal varices and Child Pugh score in the meta-regression analysis between warfarin/heparin and DOACs performed on each outcome., Conclusions: DOACs are associated with a lower incidence of bleeding and may be an attractive therapeutic option in patients with cirrhosis., (© 2020 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Background/objectives: Long-term oral anticoagulant therapy is recommended for patients with hypertrophic cardiomyopathy (HCM) who develop atrial fibrillation (AF) to prevent cardioembolic complications. In patients with non-valvular AF, direct oral anticoagulants (DOACs) has been proved to be non-inferior to adjusted-dose vitamin K antagonist (VKA). However, the role of DOACs in patients with AF in the setting of HCM has not been fully established. Methods: A comprehensive literature review was conducted by searching for published articles indexed in MEDLINE and EMBASE databases from inception through 1 May 2019. Eligible studies must start with recruitment of patients with AF in the setting of HCM who received either DOACs or VKA. The studies must follow them for the occurrence of ischaemic stroke. Hazard ratio (HR) and confidence interval (CI) of developing ischaemic stroke between the two groups must be reported. Pooled HR was calculated using a random-effect, generic inverse variance method of DerSimonian and Laird. Results: A total of three retrospective cohort studies with 4,418 participants met the eligibility criteria and were included into the meta-analysis. A significantly lower risk of all-cause death was observed in the DOACs group than in the VKA group with the pooled HR of 0.43 (95% CI, 0.33-0.58, I  = 0%). However, the risk of ischaemic stroke among patients with AF and HCM who received DOACs was not significantly different from those who received VKA with the pooled HR of 0.95 (95% CI, 0.73-1.22, 2  = 0%). Both major bleeding and intracranial bleeding were also not significantly different between those who received DOACs versus those who received VKA with the pooled HR of 0.94 (95% CI, 0.70-1.26, I 2  = 0%). Both major bleeding and intracranial bleeding were also not significantly different between those who received DOACs versus those who received VKA with the pooled HR of 0.94 (95% CI, 0.70-1.26, I The current study found that the risk of all-cause death was significantly reduced but the risk of ischaemic stroke, major bleeding and intracranial bleeding were not significantly different between patients with AF and HCM who had received DOACs and those who received VKA.2  = 0%) and 0.61 (95% CI, 0.27-1.37, I 2  = 0%), respectively. Conclusions: The current study found that the risk of all-cause death was significantly reduced but the risk of ischaemic stroke, major bleeding and intracranial bleeding were not significantly different between patients with AF and HCM who had received DOACs and those who received VKA.

Background: Chronic heart failure (CHF) is characterized by higher rates of atrial fibrillation (AF) and endothelial dysfunction (ED). First line anticoagulant therapy in AF is represented by direct oral anticoagulants (DOACs); several patients, however, are still treated with vitamin-K inhibitors. The use of DOACs is associated in previous studies with an improved vascular function. We therefore sought to evaluate possible changes in endothelial function assessed by flow-mediated dilation (FMD) in patients with CHF and AF shifting from warfarin to DOACs., Methods: Forty-three consecutive outpatients were enrolled in the study. FMD was assessed at baseline and after 4 months. Patients were compared according to AC therapy., Results: After the first measurement of FMD, 18 patients "switched" to DOACs because of poor compliance to warfarin therapy or time in therapeutic range, 19 patients continued to use DOACs, 6 warfarin. "Switched" patients to DOACs therapy showed an improved FMD (19.0 ± 6.6% vs 3.8 ± 1.3%, p < 0.0001); C-reactive protein (CRP) levels decreased in "switched" patients from 1.4 ± 0.5 to 1.0 ± 0.7 mg/dl (p < 0.05). FMD and CRP changes were not significant in patients who did not changed anticoagulant therapy. In switched patients, changes in CRP levels were proportional to FMD changes (r = -0.50, p < 0.05). Shifting from warfarin to DOACs was significantly correlated to improved FMD levels even at multivariable analysis (p < 0.05)., Conclusions: Switch from warfarin to DOACs in patents with CHF and AF was associated in an observational non randomized study with an improved endothelial function. Changes in FMD values were related to changes in CRP levels., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Edoxaban is an oral anticoagulant drug and a direct factor Xa inhibitor. However, it is still not fully understood if and how edoxaban impacts platelet function. This prospective study aimed to assess in vitro platelet function in patients with atrial fibrillation (AF) receiving edoxaban. It was a single centre study quantifying platelet aggregation in 20 patients treated with edoxaban by light transmission aggregometry. The thrombin receptor activating peptide (TRAP)-induced platelet aggregation was significantly lower 2 h after taking edoxaban compared to baseline value (44.7 ± 32.03% vs. 73.3 ± 25.55%; p < 0.0001). In addition, we did not find any significant difference in results between the patient groups.The TRAP-induced platelet aggregation is reduced in non-valvular AF patients receiving edoxaban.

Oral anticoagulants (OACs) are high-priority medications, frequently used with clinically important benefit and serious harm. Our objective was to compare the safety and effectiveness of direct-acting oral anticoagulants (DOACs) versus warfarin in a population where anticoagulation management and DOACs were readily available. A retrospective cohort study of all adults living in British Columbia with a diagnosis of atrial fibrillation and a first prescription for an OAC was conducted. Co-primary outcomes were ischemic stroke and systemic embolism, and major bleeding. Secondary outcomes included a net clinical outcome composite and analysis of discontinuation, switching, and key subgroups. We estimated the effects of treatment using time-to-event models with high-dimensional propensity score adjustment to control confounding. After adjustment for prescribing bias, a cohort (n = 20,113, 43.8% female, mean age 72.4 years) with a mean follow-up of 18.1 months showed that patients taking warfarin tended to be poorer, sicker, and less likely to have a cardiologist prescriber. Outcome event rates were not significantly different for DOACs compared to warfarin [adjusted rate ratio of 1.15 (0.91, 1.46) for systemic embolism, 0.94 (0.82, 1.08) for major bleeding, and 0.98 (0.90, 1.06) for net clinical outcome]. Only the effect of age on net clinical outcome met our strict criteria for predicting which group might be superior. Switch of drug class was associated with increased risk of events (p < 0.003). In this population, we found no difference in important clinical outcomes between warfarin and DOACs. Switching compared to not switching was associated with harm., Competing Interests: The authors declare no conflict of interest, (© 2020 Journal of Population Therapeutics and Clinical Pharmacology. All rights reserved.)

The non-vitamin K antagonist oral anticoagulants (NOACs) have considerably changed clinical practice and are increasingly being used as an alternative to vitamin K antagonists (VKAs) for 3 main reasons: 1) an improved benefit-risk ratio (in particular lower rates of intracranial bleeding), 2) a more predictable effect without the need for routine monitoring, and 3) fewer food and drug interactions compared with VKAs. Currently, there are four NOACs available: the factor Xa inhibitors apixaban, edoxaban, and rivaroxaban, and the thrombin inhibitor dabigatran. This consensus paper reviews the properties and usage of NOACs in a number of high-risk patient populations, such as patients with chronic kidney disease, patients ≥80 years of age and others and provides guidance for the use of NOACs in patients at risk of bleeding.

The availability of direct oral anticoagulants has caused a paradigm shift in the management of thrombosis. Rivaroxaban and apixaban are 2 direct oral anticoagulants whose target specificity is activated factor X (FXa). However, it is still not fully understood if and how xabans impact platelet function. This observational study aimed to assess the in vitro platelet function in patients with atrial fibrillation receiving xabans. This was a single-center study quantifying platelet aggregation in 41 patients treated with apixaban or rivaroxaban by light transmission aggregometry. The thrombin receptor activating peptide (TRAP)-induced platelet aggregation was significantly lower 2 hours after taking rivaroxaban or apixaban compared to baseline value (56.15% [8.53%] vs 29.51% [12.9%]; P = .000). Moreover, concomitant use of angiotensin-converting enzyme blockers, proton pump inhibitors, and statins reduces the efficiency of xabans. The TRAP-induced platelet aggregation was reduced in patients with cardiovascular disease 2 hours after receiving xabans.

Background: Apixaban is a direct oral anticoagulant (DOAC) for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). Other DOACs require renal dose adjustments based solely on creatinine clearance. Apixaban differs in that its dose adjustments are more complex, potentially leading to prescribing errors., Objective: To determine if adherence to Food and Drug Administration (FDA)-approved dosing for apixaban is maintained in hospitalized patients with NVAF., Methods: Patients ≥18 years old with NVAF who received apixaban during admission to 1 of 3 hospitals were evaluated. The primary outcome was to determine if providers order apixaban in accordance with FDA-approved dosages. Secondary outcomes included determining if pharmacist review increased the number of orders in accordance with FDA-approved dosing, which of the 3 criteria (age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL) were met in patients receiving off-label dosing, and the rationale for off-label prescribing., Results: A total of 556 patients met inclusion criteria. Apixaban was dosed according to FDA labeling by providers in 83.4% (n = 464) of orders. After pharmacist review, 87.0% (n = 484) of orders were at the approved dose, 12.2% (n = 68) were underdosed, and 0.7% (n = 4) were overdosed. Most patients who were underdosed met only 1 dose reduction criterion-most commonly age ≥80 years (56.0%). Reasons for off-label dosing included home dose continuation (39.0%), history of or perceived bleeding risk (30.5%), or unspecified/other (30.5%)., Conclusions: The majority of apixaban orders for NVAF were based on FDA-approved dosages after provider entry and pharmacist review.

Purpose: Limited data are available from the Australian setting regarding bleeding in patients with atrial fibrillation (AF) receiving antithrombotic therapy. We aimed to investigate the incidence of hospital admissions due to bleeding and factors associated with bleeding in patients with AF who received antithrombotic therapy., Methods: A retrospective cohort study was conducted involving all patients with AF admitted to the Royal Hobart Hospital, Tasmania, Australia, between January 2011 and July 2015. Bleeding rates were calculated per 100 patient-years (PY) of follow-up, and multivariable modelling was used to identify predictors of bleeding., Results: Of 2202 patients receiving antithrombotic therapy, 113 presented to the hospital with a major or minor bleeding event. These patients were older, had higher stroke and bleeding risk scores and were more often treated with warfarin and multiple antithrombotic therapies than patients who did not experience bleeding. The combined incidence of major and minor bleeding was significantly higher in warfarin- versus direct-acting oral anticoagulants (DOAC)- and antiplatelet-treated patients (4.1 vs 3.0 vs 1.2 per 100 PY, respectively; p = 0.002). Similarly, the rate of major bleeding was higher in patients who received warfarin than in the DOAC and antiplatelet cohorts (2.4 vs 0.4 vs 0.6 per 100 PY, respectively; p = 0.001). In multivariate analysis, increasing age, prior bleeding, warfarin and multiple antithrombotic therapies were independently associated with bleeding., Conclusion: The overall rate of bleeding in this cohort was low relative to similar observational studies. The rate of major bleeding was higher in patients prescribed warfarin compared to DOACs, with a similar rate of major bleeding for DOACs and antiplatelet agents. Our findings suggest potential to strategies to reduce bleeding include using DOACs in preference to warfarin, and avoiding multiple antithrombotic therapies in patients with AF.