Bleeding In Atrial Fibrillation Patients Research Articles

Risk of death, thrombotic and hemorrhagic events in patients with atrial fibrillation and systemic autoimmune diseases

Abstract Background Growing evidence showing that systemic autoimmune diseases (SAD) are associated with a high risk of incident atrial fibrillation (AF). However, the impact of SAD on the clinical course of AF patients is largely unknown. Purpose To assess the risk of all-cause death, thrombotic events, and bleeding in AF patients with SAD. Methods Retrospective cohort study within a global health care network (TriNetx). Using ICD codes, AF patients were categorized into two groups: 1) AF patients with SAD (M32: Systemic Lupus Erythematosus; M33: Dermato-polymyositis; M34: Systemic Sclerosis; M35: Sjogren syndrome), and 2) AF controls (without systemic autoimmune, autoinflammatory, or rheumatic diseases). The primary outcomes were the 5-year risks of 1) all-cause death, 2) thrombotic events (ischemic stroke, transient ischemic attack, peripheral arterial thromboembolism, acute myocardial infarction, deep vein thrombosis, and pulmonary embolism), and 3) hemorrhagic outcome (intracranial hemorrhage and gastrointestinal bleeding). Secondary outcomes were each component of the composite primary outcomes. Cox regression analysis before and after propensity-score-matching (PSM) was used to estimate HR and 95% confidence interval (95%CI). Sensitivity analyses were done to investigate the risk of primary outcomes associated with each systemic autoimmune disease and with different types of oral anticoagulant (OAC). Results We identified 22,371 AF patients with SAD (67.7±13.7 years, 72.2% females), and 1,478,693 AF controls (69.7±14.0, 42.6% females). Before PSM, AF patients with SAD were younger, more often females, and with a higher prevalence of cardiovascular risk factors; no differences were found after PSM. After PSM, AF patients with SAD showed a higher risk of all-cause death (HR 1.21, 95% 1.17-1.25), thrombotic events (HR 1.55, 95%CI 1.49-1.61), and hemorrhagic events (HR 1.39, 95%CI 1.32-1.46) compared to AF controls (Table 1). On sensitivity analyses, we found that the risk of primary outcomes in AF patients with SAD was independent from the OAC type, but NOAC was more effective than warfarin in reducing the risk of thrombotic events. The highest risk of all-cause death was associated with Systemic Sclerosis, while the highest risk of composite thrombotic events was associated with Systemic Lupus Erythematosus, and Dermato-polymyositis. The highest risk of stroke was associated with Sjogren syndrome; and myocardial infarction and deep vein thrombosis with Dermato-polymyositis, Systemic Lupus Erythematosus was associated with the highest risk of Intracranial hemorrhage, while Systemic Sclerosis to the highest risk of gastrointestinal bleeding (Table 2). Conclusion In AF patients the coexistence of SAD is associated with a high risk of all-cause death, thrombotic events, and bleeding. A personalized approach aimed to minimize the impact of SAD on the clinical course of AF patients is needed.Figure 1Figure 2

Non-alcoholic fatty liver disease in patients with atrial fibrillation: a report from a global federated health network

Abstract Background Few data are available on the clinical course of patients with Atrial Fibrillation (AF) and Nonalcoholic Fatty Liver Disease (NAFLD). Purpose To evaluate the 1-year risk of all-cause death, thromboembolic events, and bleeding in AF patients with NAFLD. Methods Retrospective cohort study within the global TriNetX platform. Patients with AF were categorized into two groups: i) AF with NAFLD and ii) AF without liver diseases. The primary outcomes were the 1-year risks of a composite outcome of i) all-cause death and thrombotic events (all-cause death, acute myocardial infarction, ischemic stroke, systemic arterial thromboembolism, deep vein thrombosis, and pulmonary embolism), and hemorrhagic outcome (intracranial hemorrhage and gastrointestinal bleeding). Secondary outcomes were each component of the composite primary outcomes. Cox regression analysis before and after propensity-score-matching (PSM) was used to estimate HR and 95% confidence interval (95%CI). Sensitivity analyses were done to investigate the risk associated with cirrhosis and type of oral anticoagulant. Results We identified 22,636 AF patients with NAFLD (69±12 years, 46.7% females) and 391,014 AF patients without NAFLD (72±12 years, 42.7% females). Before PSM, AF patients with NAFLD were younger, and with a higher prevalence of cardiovascular risk factors than those without liver disease. After PSM, no difference was found between the two groups, but NAFLD patients showed a higher 1-year risk of thrombotic (HR 1.54, 95%CI 1.47-1.61) and hemorrhagic (HR 1.56, 95%CI 1.42-1.72) composite outcomes (Figure 1). The higher risk in NAFLD was consistent also for all the secondary outcomes (Figure 1). On the sensitivity analyses (Figure 2), a progressively increased risk of thrombotic and hemorrhagic events was found in non-cirrhotic and cirrhotic patients compared to patients without liver diseases, whereas non-vitamin-k antagonist (NOAC) seems to be safer and more effective than warfarin. Conclusion In AF patients, NAFLD is associated with a higher 1-year risk of all-cause death, thrombotic and hemorrhagic events. Further studies are needed to establish the best clinical approach to manage NAFLD in AF patients.Figure 1Figure 2

Dynamic assessment of CHA2DS2-VASc and HAS-BLED scores for predicting ischemic stroke and major bleeding in atrial fibrillation patients

Introduction and objectivesStroke and bleeding risks in atrial fibrillation (AF) are often assessed at baseline to predict outcomes years later. We investigated whether dynamic changes in CHA2DS2-VASc and HAS-BLED scores over time modify risk prediction. MethodsWe included patients with AF who were stable while taking vitamin K antagonists. During a 6-year follow-up, all ischemic strokes/transient ischemic attacks (TIAs) and major bleeding events were recorded. CHA2DS2-VASc and HAS-BLED were recalculated every 2-years and tested for clinical outcomes at 2-year periods. ResultsWe included 1361 patients (mean CHA2DS2-VASc and HAS-BLED 4.0±1.7 and 2.9±1.2). During the follow-up, 156 (11.5%) patients had an ischemic stroke/TIA and 269 (19.8%) had a major bleeding event. Compared with the baseline CHA2DS2-VASc, the CHA2DS2-VASc recalculated at 2 years had higher predictive ability for ischemic stroke/TIA during the period from 2 to 4 years. Integrated discrimination improvement (IDI) and net reclassification improvement (NRI) showed improvements in sensitivity and better reclassification. The CHA2DS2-VASc recalculated at 4 years had better predictive performance than the baseline CHA2DS2-VASc during the period from 4 to 6 years, with an improvement in IDI and an enhancement of the reclassification. The recalculated HAS-BLED at 2-years had higher predictive ability than the baseline score for major bleeding during the period from 2 to 4 years, with significant improvements in sensitivity and reclassification. A slight enhancement in sensitivity was observed with the HAS-BLED score recalculated at 4 years compared with the baseline score. ConclusionsIn AF patients, stroke and bleeding risks are dynamic and change over time. The CHA2DS2-VASc and HAS-BLED scores should be regularly reassessed, particularly for accurate stroke risk prediction.

Risk of major cardiovascular events and bleeding in atrial fibrillation patients with chronic obstructive pulmonary disease treated with low dose azithromycin prophylaxis

Abstract Background Chronic obstructive pulmonary disease (COPD) is associated with an increased risk of cardiovascular events in patients with atrial fibrillation (AF). Low Dose Azithromycin Prophylaxis (LDAP) is associated with improved outcomes in people suffering frequent exacerbations of COPD, but the widespread use of macrolides in patients with underlying cardiovascular disease has been debated due to safety concerns. Aims and Objectives To investigate the safety and efficacy of LDAP in AF patients with COPD in a large global federated dataset. Methods We conducted a retrospective cohort study within the global TriNetX Platform, including AF patients with COPD exacerbations. Risks for all-cause death, major adverse cardiovascular events (MACE: acute coronary syndrome, thromboembolic events, severe ventricular arrhythmias, and heart failure), intracranial hemorrhage (ICH) and gastrointestinal (GI) bleeding were recorded up to 30 days post-COPD exacerbations and compared between LDAP users (at least 3 months use and using LDAP at index) and an active control group (non-Azithromycin users receiving inhaled corticosteroids (ICS)). Cox regression analyses compared outcomes between groups after propensity-score-matching (PSM) for cardiovascular risk factors. Results We identified 2791 LDAP users with COPD and AF (mean age 71.5±10.6 years, 48.9% female), and 61054 controls. Before PSM, LDAP users showed a lower prevalence of cardiovascular risk factors and were less likely to be prescribed oral anticoagulation (68.1% vs 76.1%, p<0.001). After PSM no significant baseline differences were found between two groups. After COPD exacerbation, LDAP users were associated with a lower 30-day risk of all-cause death (HR: 0.72, 95%CI 0.60-0.97), MACE (HR 0.72, 95%CI 0.57-0.90), ICH (0.48, 95%CI 0.27-0.88) and GI bleeding (HR 0.69,95%CI 0.46-0.89) compared to the conventional treatment with ICS. Analysing the different time frames, the lower risk of thrombotic events was observed during the second week after COPD exacerbation while the magnitude of the bleeding risk reduction was more evident in the first 7 days (Figure 1). Conclusion LDAP use is associated with a lower risk of all-cause death, MACE and bleeding in AF patients with COPD. Further studies are needed to investigate the possible role of LDAP as part of the integrated care management of AF patients with COPD.

Efficacy and safety of under-dose non-vitamin K antagonist oral anticoagulant with atrial fibrillation undergoing PCI: Insights from a nationwide population-based cohort study

Abstract Background The under-dose non-vitamin K antagonist oral anticoagulants (NOACs) are required according to clinical conditions for patients with atrial fibrillation (AF). We aimed to assess the comparative effectiveness and safety of standard-dose and under-dose NOACs undergoing PCI. Methods We studied the retrospective nonrandomized observational cohort of oral anticoagulant native nonvalvular patients with atrial fibrillation treated NOACs (rivaroxaban, dabigatran, apixaban, or edoxaban) from January 2013 to December 2017, based on the Korean Health Insurance Review and Assessment database. We performed head-to-head comparisons of standard-dose and under-dose NOACs. Results We studied standard-dose and under-dose NOACs were 1,095 and 2,136, respectively (Rivaroxaban, 500 vs 782; Dabigatran, 233 vs 709; Apixaban, 244 vs 430; Edoxaban, 118 vs 214). Compared with standard-dose NOACs, low-dose NOACs were associated with lower risk of major bleeding in AF patients with PCI(Rivaroxaban, HR=0.72[0.58∼0.85]; Dabigatran, HR=0.73[0.60-0.86]; Apixaban, HR=0.82[0.69-0.95]; Edoxaban, HR=0.85[0.72-0.98]. Also, the ischemic stroke was significantly different for standard-dose and under-dose NOACs in AF patients with PCI (Rivaroxaban, HR=0.67[0.54-0.80]; Dabigatran, HR=0.68[0.55-0.81]; Apixaban, HR=0.69[0.56-0.82]; Edoxaban, HR=0.70[0.57-0.83]). Conclusions In this nonrandomized Asian cohort study, NOACs(rivaroxaban, dabigatran, apixaban, or edoxaban) were associated with lower risk of major bleeding and ischemic stroke for standard-dose and under-dose NOACs in AF patients with PCI.Table 1.Clinical outcomes

Abstract 14037: Nonspecific Tools Performed Better in Discriminating Major Bleeding From Direct Oral Anticoagulants Than Specific Tools in a Real-World Population With Atrial Fibrillation

Background. Direct oral anticoagulants (DOACs) are the first-line guideline-recommended therapy for preventing stroke in non-valvular atrial fibrillation (AF) patients. DOACs are increasingly being prescribed in the US compared to warfarin because of lower bleeding risk overall, but the proportion of Emergency Department visits involving DOACs-related bleeding increased from 2.3% in 2011 to 37.9% in 2017. Therefore, tools that accurately predict bleeding risk from DOACs are needed. Aim. This study compared the performance of six tools for predicting major bleeding risk in non-valvular AF patients on DOACs. Methods. A retrospective cohort study was carried out with 2,364 Caucasians diagnosed with non-valvular AF and treated with rivaroxaban or apixaban at the University of Michigan Health System. Bleeding risk was calculated using six existing tools: CHA 2 DS 2 -VASc, Anticoagulation-specific Bleeding Score (ABS), HAS-BLED, ATRIA, HEMORR2HAGES, and ORBIT. Major bleeding events were retrieved from medical records and classified according to International Society of Thrombosis and Haemostasis criteria. Discrimination was estimated using the c-statistic, and the areas under the curves (AUC) were compared using the Hanley-McNeil test. RGui was used for all statistical analyses and p-values <0.05 were considered statistically significant. Results. A total of 97 (4.1%) patients experienced major bleeding on DOACs over 2.27 ± 2.03 years of follow-up. HAS-BLED and ABS are tools for specifically predicting major bleeding risk, but both had significantly lower performance than ATRIA, HEMORR2HAGES, and ORBIT ( Figure 1 ). There was no significant difference in the discriminative performance between HAS-BLED and ABS, as well as between ATRIA, HEMORR2HAGES, and ORBIT. Conclusion. ATRIA, HEMORR2HAGES, and ORBIT were the tools that performed better in discriminating major bleeding in AF patients if compared to HAS-BLED and ABS.

Comparative validation of the HAS-BLED and the GARFIELD-AF bleeding risk scores in Asian patients with atrial fibrillation: a report from the COOL-AF registry

Abstract Introduction There have been conflicting comparative data on the predictive value of the HAS-BLED and the GARFIELD-AF bleeding risk scores. Furthermore, there are limited data in Asian patients with atrial fibrillation (AF) who are at higher risk of bleeding compared to non-Asians. We compared the performance of the HAS-BLED score with the GARFIELD-AF score in predicting major bleeding in AF patients treated with OAC in the Cohort of antithrombotic use and Optimal INR Level in patients with non-valvular AF in Thailand (COOL-AF) registry. Since the sex and body weight seem to impact bleeding events in Asians, we explored an update of the HAS-BLED risk score by incorporating sex and body weight. Methods The COOL-AF registry was a nationwide study enrolling AF patients from 27 hospitals in Thailand between 2014 and 2017. The registry aimed to assess antithrombotic patterns, quality of oral anticoagulant (OAC) control and clinical outcomes. Data were collected every 6 months and until 3 years. AF patients treated with oral anticoagulants (OAC, either warfarin or non-vitamin K antagonist OAC (NOAC)) were included into the present study. We fitted the variables of the HA-SBLED and GARFILED-AF score to major bleeding in Cox regression model. We also explored a modified HAS-BLED by addition of two additional predictors (sex and body weight). Discrimination, calibration, net reclassification index and decision curve analysis were used to compare the predictive performance of the three models. Results Of 3,402 patients in the COOL-AF registry, 2,568 patients (mean age 68.4 years; 43.4% female) who received OAC at baseline were studied. The proportion of patients with prior bleeding was 10.6%. Majority of patients (68.7%) received warfarin. The incidence rate of major bleeding was 2.11 (1.79–2.48) per 100 person-years. The C-indexes of the GARFIELD-AF, HASBLED and modified HASBLED score were 0.65 (95% CI 0.63–0.67), 0.66 (95% CI 0.64–0.68) and 0.69 (95% CI 0.67–0.71) respectively. Calibration plot showed good agreement between predicted and observed bleeding in the deciles of original HAS-BLED and GARFIELD-AF scores, while the modified HAS-BLED score overestimated the risk in the last decile (Figure 1). The modified HASBLED score has superior NRI than the original HASBLED score (26.9%, 95% CI 9.7% to 42.2%). The NRI between the modified HASBLED and GARFIELD score was similar (20%, 95% CI −1.2% to 40.4%). The net benefit curve of the three models were overlapping among different risk thresholds (Figure 2). Conclusion The clinical utility for bleeding prediction GARFIELD-AF, HAS-BLED and modified HAS-BLED scores were similar in Asian patients with AF participating in the COOL-AF registry. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): This study was funded by the Health Systems Research Institute (HSRI) (grant no. 59-053), the HeartAssociation of Thailand under the Royal Patronage of H.M. the King.

Association between concurrent use of diltiazem and DOACs and risk of bleeding in atrial fibrillation patients.

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. We conducted a population-based, nested case-control study in Ontario, Canada. The study population included all patients with AF > 66years 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 7days); (b) recent users (diltiazem use within 8 to 90days); and (c) unexposed (no diltiazem prescription or diltiazem prescription > 90days before index date). Conditional logistic regression models were used to examine the association between bleeding and diltiazem co-prescription. Among 86,679 AF patients on a DOAC, the median age of AF patients was 80years (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. Current use of diltiazem was associated with major bleeding among AF patients receiving a DOAC.

Assessment of one-year risk of ischemic stroke versus major bleeding in patients with atrial fibrillation

BackgroundPatients diagnosed with atrial fibrillation (AF) are at increased risk of stroke. Several guidelines to assess the risk of ischemic stroke and major bleeding in AF patients have been published. The CHA2DS2-VASc score has been adopted widely for predicting stroke within one year of the index AF diagnosis and is used to guide the prescription of anticoagulants. Anticoagulation therapy increases the risk of bleeding and scoring systems such as HAS-BLED assess the risk of major bleeding in anticoagulated patients. Despite these advances, no study has examined the risks of the two outcomes simultaneously. How patients’ fear of particular outcomes affects these risks also remains unknown. MethodsWe incorporated the risks of ischemic stroke and major bleeding within one year of the index AF admission as well as the fear of stroke and bleeding of each individual patient. The patients enrolled in this retrospective observational study were identified using hospital admission data from the Myocardial Infarction Data Acquisition System (MIDAS), a statewide database including all hospitalizations for cardiovascular disease in New Jersey. Probabilities of the outcomes (ischemic stroke, major bleeding, both, or neither within one year of the index AF admission) were estimated using multinomial regression with patient demographics and comorbidities (heart failure [HF], hypertension [HTN], diabetes mellitus [DM], anemia, chronic obstructive pulmonary disease [COPD], kidney disease [KD], prior stroke or transient ischemic attack [TIA]) as predictors. These estimates were used in a Deming regression to model the association of ischemic stroke and major bleeding in grouped patients. The assessment of the importance of each outcome was superimposed on the final model to arrive at a recommendation for anticoagulation therapy. ResultsThe results of the Deming regression indicated a positive relationship between ischemic stroke and major bleeding (slope = 1.67, 95% confidence interval [CI] 1.37 to 1.97). Estimates of the risks of the two outcomes and the lines of best fit from Deming regression were determined. This model for risk assessment of stroke and major bleeding within one year of the index AF hospital admission combined objective data and subjective assessment of the relative fear of stroke versus bleeding by each hypothetical patient on 0–100 scale. Examples with the fears of stroke versus major bleeding being equal (50-50) and a higher fear of stroke (80–20) are presented. ConclusionsThe new model for risk assessment of ischemic stroke and major bleeding within one year of the index AF hospital admission proposed in this work used objective, empirically driven measures, and subjective assessment of the outcomes’ importance for individual patients. Such models may assist physicians in their decision making regarding anticoagulation therapy.

Yearly Incidence of Stroke and Bleeding in Atrial Fibrillation with Concomitant Hyperthyroidism: A National Discharge Database Study.

Background: Hyperthyroidism is associated with atrial fibrillation (AF), and the latter is a major risk factor for stroke. Aim: We aimed to investigate the yearly incidence of stroke and bleeding in AF patients with and without concomitant hyperthyroidism from the French National Hospital Discharge Database. Methods: Admissions with AF between January 2010 and December 2019 were retrospectively identified and retrieved from the French national database. Incidence rates of ischaemic stroke and bleeding were compared in AF patients with and without concomitant hyperthyroidism. The associations of risk factors with ischaemic stroke were assessed by Cox regression. Results: Overall 2,421,087 AF patients, among whom 32,400 had concomitant hyperthyroidism were included in the study. During the follow-up (mean: 2.0 years, standard deviation SD: 2.2 years), the yearly incidence of ischaemic stroke was noted to be 2.6 (95% confidence interval CI: 2.5–2.8) in AF patients with concomitant hyperthyroidism, and 2.3 (95%CI: 2.3–2.4) in non-thyroid AF patients. Hyperthyroidism was noted as an independent risk factor for ischaemic stroke (adjusted hazard ratio aHR: 1.133, 95%CI: 1.080–1.189) overall, particularly within the first year of hyperthyroidism diagnosis (aHR 1.203, 95%CI 1.120–1.291), however, the association became non-significant in subsequent years (aHR 1.047, 95%CI 0.980–1.118). Major bleeding incidence was lower in the hyperthyroid AF group in comparison to the non-thyroid AF group (incidence ratio: 5.1 vs. 5.4%/year, p < 0.001). The predictive value of CHA2DS2VASc and HAS-BLED scores for ischaemic stroke and bleeding events, respectively, did not differ significantly between AF patients with or without concomitant hyperthyroidism. Conclusions: Hyperthyroidism seems to be an independent risk factor of ischaemic stroke in AF patients, particularly within the first year of hyperthyroidism diagnosis.

Latest outcomes of transcatheter left atrial appendage closure devices and direct oral anticoagulant therapy in patients with atrial fibrillation over the past 5 years: a systematic review and meta-analysis

Left atrial appendage closure (LAAC) are emerging treatment for patients with atrial fibrillation (AF). However, data on the safety, efficacy, and medications for LAAC devices in patients with AF are lacking. We aimed to investigate the incidence of all-cause mortality, stroke, and major bleeding in AF patients with LAAC devices and DOACs. Moreover, we aimed to investigate the incidence rate of device-related thrombus (DRT) and the medications used in the management of AF patients with LAAC devices to gain insights into achieving better outcome. Based on a literature search using PubMed, EMBASE, Cochrane Library, and Web of Science databases between January 2015 and December 2020, eight LAAC device studies that used WATCHMAN and Amulet, and three DOAC studies that used rivaroxaban, with a total of 24,055 AF patients (LAAC devices, n = 2855; DOAC, n = 21,200), were included. A random-effects model was used to incorporate heterogeneity among studies. The pooled incidence of events per person-years were as follows: all-cause mortality, 0.06 (95% confidence interval [CI] 0.02–0.10) for WATCHMAN, 0.04 (95% CI 0.00–0.14) for Amulet, and 0.03 (95% CI 0.01–0.04) for rivaroxaban; stroke; 0.02 (95% CI 0.00–0.04) for WATCHMAN, 0 for Amulet, and 0.01 (95% CI 0.01–0.02) for rivaroxaban; major bleeding, 0.04 (95% CI 0.02–0.06) for WATCHMAN, 0.02 (95% CI 0.00–0.06) for Amulet, and 0.02 (95% CI 0.01–0.03) for rivaroxaban. The incidence rate of DRT was 2.3%, and complications were reported in 9%. The incidence of all-cause mortality, stroke, and major bleeding were similar between LAAC devices and DOACs. The rate of complications was acceptable, and those of DRT were lower than the average incidence reported in previous studies. However, further follow-up is needed. Concomitant anticoagulant and antiplatelet therapies should be further evaluated to find the optimal regimen for AF patients with LAAC devices.

Ischaemic and bleeding risk in atrial fibrillation with and without peripheral artery disease and efficacy and safety of full- and half-dose edoxaban vs. warfarin: insights from ENGAGE AF-TIMI 48.

In patients with atrial fibrillation (AF), peripheral artery disease (PAD) is associated with higher rates of stroke and bleeding. Both higher dose edoxaban (60/30mg) and lower dose edoxaban (30/15mg) were non-inferior to warfarin for stroke and systemic embolism (SSE) and significantly reduced major bleeding in AF patients in the global study to assess the safety and effectiveness of edoxaban vs standard practice of dosing with warfarin in patients with atrial fibrillation (ENGAGE AF-TIMI 48) trial. Whether the efficacy and safety of these dosing strategies vs. warfarin are consistent in patients with AF and PAD has not been described. Of 21 105 patients with AF randomized to warfarin, edoxaban 60/30mg, or edoxaban 30/15mg, 841 were identified with PAD. Endpoints included major adverse cardiovascular events (MACEs), SSE, and major bleeding. Patients with PAD had higher risk of MACEs [adjusted hazard ratio (HRadj) 1.33, 95% confidence interval (CI) 1.12-1.57, P = 0.001] and cardiovascular (CV) death (HRadj 1.49, 95% CI 1.21-1.83, P &lt; 0.001) than those without PAD, but not major bleeding. The efficacy of edoxaban 60/30mg vs. warfarin was consistent regardless of PAD (SSE HR; PAD 1.16, 95% CI 0.42-3.20; no-PAD 0.86, 95% CI 0.74-1.02, P-interaction 0.57) as was major bleeding (PAD 0.96, 95% CI 0.54-1.70; no-PAD 0.80, 95% CI 0.70-0.91, P-interaction 0.54). Edoxaban 30/15mg was inferior for SSE, with significant heterogeneity when stratified by PAD status (P-interaction 0.039). Patients with AF and PAD are at heightened risk of MACEs and CV death vs. those without PAD. The efficacy and safety of edoxaban 60/30mg vs. warfarin in AF are consistent regardless of PAD; however, edoxaban 30/15mg is inferior for stroke prevention in AF patients with PAD. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT00781391.

Associations of anemia with death and major bleeding in patients with atrial fibrillation: A report from the Chinese Atrial Fibrillation Registry Study

BackgroundAnemia is a common comorbidity in patients with atrial fibrillation (AF). Reports on the association of anemia and adverse events in patients with AF, especially from Asia, are limited.Methods and ResultsBased on data from the Chinese Atrial Fibrillation Registry Study (CAFR), a total of 18,106 AF patients enrolled between August 2011 and December 2018 had hemoglobin (Hb) values recorded at baseline. Patients were classified into three groups according to Hb levels: 15,606 patients (86.2%) into the no anemia group (male Hb≥130 g/L; female Hb≥120 g/L), 1800 (9.9%) with mild anemia (male 110≤Hb<129 g/L; female 110≤Hb<119 g/L), and 700 (3.9%) with moderate to severe anemia (Hb≤109 g/L). Multivariable Cox regression models were used to determine if anemia was independently associated with all‐cause death, cardiovascular death, or major bleeding, after adjusting for confounders.Anemia was present in 13.8% of the population at baseline. During a median follow‐up of 4.01 years, the incidences of all‐cause death (1.8, 4.9, and 8.9 per 100 person‐years), cardiovascular death (1.0, 2.9, and 4.5 per 100 person‐years), and major bleeding (0.5, 0.6, and 0.7 per 100 person‐years) were gradually accentuated in patients with no anemia, mild anemia, and moderate to severe anemia, respectively. Compared with patients with no anemia, those with anemia had higher risks for all‐cause death (mild anemia; adjusted hazard ratio [HR]: 1.22, 95% confidence interval [CI]: 1.08–1.38; moderate to severe anemia; adjusted HR: 1.53, 95% CI: 1.31–1.77); and cardiovascular death (mild anemia; adjusted HR: 1.29, 95% CI: 1.10–1.52; moderate to severe anemia; adjusted HR: 1.27, 95% CI: 1.03–1.57), but not for major bleeding. The association between anemia and all‐cause death was similar among subgroups stratified by sex, kidney function, anticoagulant, or ablation therapy.ConclusionsAnemia was associated with increased risks of all‐cause death, cardiovascular death, but no major bleeding in AF patients. The effect of anemia correction on the prognosis of patients with AF requires further study.

Drug-drug interactions in atrial fibrillation patients receiving direct oral anticoagulants

Polypharmacy is common in patients with atrial fibrillation (AF), making these patients vulnerable to the occurrence of potential drug-drug interactions (DDIs). We assessed the risk of ischemic stroke and major bleeding in the context of concomitant treatment with potential DDIs in patients with AF prescribed direct oral anticoagulants (DOACs). Using the common data model (CDM) based on an electronic health record (EHR) database, we included new users of DOACs from among patients treated for AF between January 2014 and December 2017 (n = 1938). The median age was 72 years, and 61.8% of the patients were males, with 28.2% of the patients having a CHA2DS2-VASc score in category 0–1, 49.4% in category 2–3, and 22.4% in category ≥ 4. The CHA2DS2-VASc score was significantly associated with ischemic stroke occurrence and hospitalization for major bleeding. Multiple logistic regression analysis showed that increased risk of ischemic stroke and hospitalization for major bleeding was associated with the number of DDIs regardless of comorbidities: ≥ 2 DDIs was associated with ischemic stroke (OR = 18.68; 95% CI, 6.22–55.27, P < 0.001) and hospitalization for major bleeding (OR = 5.01; 95% CI, 1.11–16.62, P < 0.001). DDIs can cause reduced antithrombotic efficacy or increased risk of bleeding in AF patients prescribed DOACs.

Abstract 9868: Novel Oral Anticoagulants versus Vitamin K Antagonists in Patients with Atrial Fibrillation and Bioprosthetic Valve Replacement: A Systematic Review and Meta-Analysis

Background: Vitamin K antagonists (VKAs) such as warfarin are traditionally prescribed in patients with atrial fibrillation (AF) and bioprosthetic valves (BPVs) to prevent thromboembolic events. However, various studies have proposed novel oral anticoagulants (NOACs) as an effective and safer option to use. Therefore, we conducted a systematic review and meta-analysis to compare their relative efficacy and safety profiles. Methods: Pubmed, Cochrane Central, and Embase were searched up until May 15, 2021 for randomized clinical trials (RCTs) and observational studies determining efficacy and safety of NOACs or VKAs in AF patients who had undergone BPV replacement. Outcomes of interest were: stroke or systemic embolism (SSE), major bleeding, all-cause mortality, and intracranial hemorrhage (ICH). Subgroup analysis by study design (RCT and observational) was performed. Summary estimates were reported as random effects risk ratios (RRs) with 95% confidence intervals (CIs). Results: A total of 12 studies (4 RCTs and 8 observational) with 6436 patients (mean age 72.1 years; 51.4% males) were included in the analysis. In comparison to VKAs, NOACs demonstrated a significant reduction in ICH (RR 0.41 [95% CI 0.25,0.67]; p=0.0003; I 2 = 0%) and major bleeding (RR 0.63 [95% CI 0.53,0.74]; p&lt;0.00001; I 2 = 0%) at a mean duration follow up of 23.8 months. However, no difference was observed in risk of SSE (RR 0.77 [95% CI 0.50,1.19]; p=0.23; I 2 = 53%) and all-cause mortality (RR 0.98 [95% CI 0.78,1.22]; p=0.84; I 2 = 15%). Observational studies and RCTs did not significantly differ across all outcomes in the subgroup analysis. Conclusions: This meta-analysis suggests that NOACs are effective at reducing risk of ICH and major bleeding in AF patients with BPVs in contrast to VKAs. Future large-scale RCTs can aid in corroborating the legitimacy of these results.

Comparison of clinical outcomes of edoxaban versus apixaban, dabigatran, rivaroxaban, and vitamin K antagonists in patients with atrial fibrillation in Germany: A real-world cohort study

BackgroundThe aim of the study was to compare the real-world effectiveness and safety in atrial fibrillation (AF) patients treated with edoxaban versus other oral anticoagulants (OACs) (apixaban, dabigatran, rivaroxaban, and vitamin K antagonists [VKA]) in Germany. Methods and resultsUsing a representative database of 3.5 million statutory health-insured lives in Germany, a retrospective cohort study was conducted to examine ischemic stroke (IS) or systemic embolism (SE) and major bleeding in AF patients initiating anticoagulant therapy from January 2014 through June 2017. Inverse probability of treatment weighting using propensity score was applied for baseline covariate adjustment. Cox proportional hazards models were used to estimate the adjusted risk (hazard ratio [HR]) of each outcome comparing edoxaban versus other OACs.Among 21,038 patients treated with OACs, 1236 edoxaban, 6053 apixaban, 1306 dabigatran, 7013 rivaroxaban, and 5430 VKA patients were included. The adjusted combined risks of IS or SE were lower (p < 0.05) for each edoxaban pairwise comparison with other OACs (HR: 0.83 vs. apixaban, 0.60 vs. dabigatran, 0.72 vs. rivaroxaban, 0.64 vs. VKA). Edoxaban favored lower risks of major bleeding compared with rivaroxaban (HR: 0.74) and VKA (HR: 0.47). No differences in the risk of major bleeding were found between edoxaban and apixaban (p = 0.33), and between edoxaban and dabigatran (p = 0.06). ConclusionsEdoxaban was associated with better effectiveness compared with other OACs in AF patients from Germany. Edoxaban also demonstrated a favorable safety profile.

Feasibility and usability of a mobile health tool on anticoagulation management for patients with atrial fibrillation: a pilot study.

Appropriate prescription of oral anticoagulants (OACs) and good patient adherence are essential to ensure optimal anticoagulation in patients with atrial fibrillation (AF). The aim of this study is to develop a mobile health tool to aid both clinicians and patients with AF in anticoagulation therapy. In this study, a novel anticoagulation management model integrating decision support and patient follow-up, the I-Anticoagulation, was developed based on a WeChat Mini Program. With this tool, the risks of stroke and bleeding in AF patients can automatically be calculated according to their characteristics. Anticoagulation regimens were recommended based on a trade-off analysis that balances stroke and bleeding risks according to recent clinical guidelines. A shared decision can be made with full communication between medical professionals and patients. Moreover, follow-up was also conducted using I-Anticoagulation. A total of 120 AF patients receiving anticoagulants (40 received warfarin and 80 received non-vitamin K antagonist oral anticoagulants [NOACs]) were included in the pilot study. The incidence of thromboembolic events was 2.5% and 1.3%, and the rates of bleeding events were 22.5% and 13.8% in the warfarin and NOAC groups, respectively. Generally, self-reported adherence was high, and the satisfaction with anticoagulation was good in all patients with AF. Overall, the anticoagulation management model developed in this study could be involved in the full process of anticoagulation therapy in AF patients to improve rationality, adherence, and satisfaction in both medical professionals and patients. However, the usability, feasibility, and acceptability of the I-Anticoagulant-based anticoagulation management model need to be further assessed through well-designed random clinical trials.

Predictors for major bleeding in elderly (75 years and over) patients with non-valvular atrial fibrillation at high risk of bleeding: sub-analysis of the ANAFIE Registry

Abstract Background In patients with atrial fibrillation (AF) receiving anticoagulant therapy, bleeding events are associated with reduced survival. Previous studies showed that bleeding events during anticoagulant therapy were more frequent in elderly AF patients than in younger patients. HAS-BLED score has been used to assess the risk of bleeding in AF patients. In patients at high bleeding risk (HAS-BLED score ≥3), we sought to identify other risk factors associated with major bleeding not included in HAS-BLED score in elderly non-valvular AF (NVAF) patients. Purpose The All Nippon Atrial Fibrillation In the Elderly (ANAFIE) Registry is a prospective, multicenter, observational study to collect real-world data on clinical status and prognosis in more than 30,000 Japanese patients (aged ≥75 y) with NVAF. This sub-analysis of the ANAFIE Registry assessed the 2-year outcomes and identified predictors for major bleeding in elderly NVAF patients with a high bleeding risk. Methods A total of 32,275 patients from the ANAFIE Registry were divided into 2 groups according to HAS-BLED score (≥3 [high-risk group] and ≤2 [reference group]). The annualized incidence rate, hazard ratio (HR) for clinical outcomes, and independent predictors for major bleeding were analyzed using Kaplan-Meier analysis and the Cox proportional-hazards model. Results A total of 6,826 patients constituted the high-risk group: mean age, 81.8 years old (75–80 years, 37.8%; 81–84 years, 33.9%; ≥85 years, 28.3%); male ratio, 72.2%; mean creatinine clearance (CrCL), 42.7 mL/min; history of major bleeding, 14.2%; presence of non-paroxysmal AF, 62.2%; mean total number of medicines used, 7.8. Anticoagulants were used in 91.2% (warfarin [WF], 29.9%; direct oral anticoagulants [DOACs], 61.2%). Proton-pump inhibitors (PPI) were administered in 46.5%. Compared to the reference group, the high-risk group had higher annualized incidence rates (/100 patient-year) of major bleeding (1.49 vs 0.97), intracranial hemorrhage (0.95 vs 0.70), gastrointestinal (GI) bleeding (2.63 vs 1.73), and all-cause mortality (5.50 vs 3.24). All-cause mortality more frequently occurred in patients aged ≥85 years compared to 75–79 years and those with CrCL &amp;lt;50 mL/min compared to CrCL ≥50 mL/min. In the high-risk group, DOAC subgroup had lower incidences of the above-mentioned outcomes other than GI bleeding than WF subgroup. The following relevant factors for major bleeding not included in HAS-BLED score were identified in the high-risk group: Body mass index (BMI) ≥25.0 kg/m2 (HR, 0.40), heart failure (HF) with reduced left ventricular ejection fraction (LVEF) (HR, 1.38), a fall within 1 year (HR, 2.29), and use of PPI (HR, 0.65). Conclusions Among elderly (≥75 years) Japanese NVAF patients in the high bleeding risk group (HAS-BLED score ≥3), HF with reduced LVEF, and a fall within 1 year were identified as independent predictors of major bleeding. BMI ≥25.0 kg/m2 and PPI use were protective for major bleeding. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Co., Ltd.

Relative Importance of Heart Failure Events Compared to Stroke and Bleeding in AF Patients.

Introduction: Incident heart failure (HF), ischemic stroke and systemic embolism (IS/SE), and major bleeding related to anticoagulation therapy are still the most frequent events occurring in patients with atrial fibrillation (AF). The aim of this study was to assess the 3-year incidence, predictors, and related mortality of IS/SE, major bleeding, and HF in a large cohort of AF outpatients. Methods and results: We studied 4973 outpatients with prevalent AF included in the CARDIONOR registry. The mean age was 72.9 ± 11.2 years, 24.1% had diabetes mellitus and 78.9% had anticoagulant therapy at baseline. The mean CHA2DS2Vasc score was 3.4 ± 1.7. After a median follow-up of 3.2 years (IQR: 2.8 to 3.5), incident HF, IS/SE and major bleeding occurred in 10.5%, 3.3% and 2.1% of patients, respectively. When analyzed as time-dependent variables, IS/SE, major bleeding and hospitalization for decompensated HF were all strongly associated with mortality. The independent predictors of incident HF were age, women, hypertension, diabetes mellitus, coronary artery disease and a previous history of HF. A sensitivity analysis in patients without history of HF at inclusion revealed that incident HF remained the most frequent adverse event, occurring in 5.3% of patients, compared to IS/SE (1.7%) and major bleeding (2.5%). Conclusion: HF is a common residual cardiovascular adverse event occurring in AF outpatients and is associated with a very high mortality. Since modifiable risk factors are associated with incident HF, upstream intensive management of these risk factors would be of interest.

Mild Renal Dysfunction and Risk of Thromboembolism and Bleeding in Patients with Atrial Fibrillation: The Chinese Atrial Fibrillation Registry Study

Abstract Objective: Previous studies indicated that patients with atrial fibrillation (AF) and moderate-to-severe chronic kidney disease (CKD) are at a higher risk of thromboembolism and bleeding during anticoagulation. Whether mild CKD is associated with an increased risk of thromboembolism and bleeding in AF patients remains unknown. This study aimed to evaluate the impact of mild CKD on thromboembolism and major bleeding among patients with AF. Methods: Baseline serum creatinine was available in 17,559 of 25,512 patients enrolled in the China-AF study between August 2011 and December 2018. After excluding those who underwent AF ablation or with moderate-to-severe CKD, 7191 non-valvular AF patients (2059 with mild CKD and 5132 with normal renal function) with regular follow-up for at least 6 months were included. Primary outcomes were the time to the first occurrence of thromboembolic and major bleeding events. Results: Over a mean follow-up of (44.4 ± 23.4) months, 639 thromboembolism and 231 major bleeding events occurred. The crude incidence rates of thromboembolism were higher in the mild CKD group than that of the normal renal function group (3.0/100 person-years vs. 2.2/100 person-years, P &lt; 0.0001), while the crude incidence rates of major bleeding were comparable between the two groups (1.0/100 person-years vs. 0.8/100 person-years, P = 0.076). After multivariate analyses, mild CKD was not associated with an increased risk of thromboembolism (HR = 1.05, 95% CI: 0.89–1.25, P = 0.547) or major bleeding (HR = 1.11, 95% CI: 0.84–1.47, P = 0.476). Conclusions: Mild CKD was not an independent risk factor of thromboembolism or major bleeding in patients with AF.