Risk Factors for Thromboembolic Events in Patients With Dialysis-Dependent CKD: Pooled Analysis of Four Global Roxadustat Phase 3 Trials.

INTRODUCTION: Risk factors for thromboembolic events in patients with dialysis-dependent chronic kidney disease (CKD) receiving roxadustat are unknown. Iron deficiency has been reported as a risk factor for thrombosis in the general population. METHODS: Thromboembolic events with onset before and after week 12 in patients receiving roxadustat were evaluated in this pooled analysis of four global phase 3 trials, PYRENEES, SIERRAS, HIMALAYAS, and ROCKIES. Baseline risk factors for thromboembolic events were investigated by Cox regression analyses. Nested case-control analyses with matched pairs of case-control data explored the relationship between thromboembolic events and last known laboratory parameters before event onset. RESULTS: Of 2354 patients, 1026 thromboembolic events were observed in 568 patients. Baseline risk factors found included hemodialysis (vs peritoneal dialysis), advanced age (≥ 65 years), Black race, high high-sensitivity C-reactive protein, and history of thromboembolism, cardiovascular disease, or diabetes. Univariate case-control analyses revealed that high hemoglobin rate of rise (≥ 0.5 g/dL/week; odds ratio [OR] 2.09; 95% confidence interval [CI] 0.98-4.46) showed a trend towards increased risk of thromboembolic events before week 12, and high rate of hemoglobin decline was associated with events after week 12 (< - 0.5 g/dL/week; OR 3.73; 95% CI 1.68-8.27) as compared to stable hemoglobin levels (≥ - 0.1 to < 0.1 g/dL/week). Multivariate case-control analyses showed that low last known hemoglobin level (< 10 g/dL: adjusted OR 1.91; 95% CI 1.04-3.50; vs ≥ 12 g/dL) and low last known transferrin saturation (TSAT < 10%: adjusted OR 3.78; 95% CI 1.71-8.39; vs ≥ 30%) before event onset were associated with events after week 12. In patients with last known TSAT < 30%, higher roxadustat dose was associated with thromboembolic events; however, no association was observed in those with TSAT ≥ 30%. CONCLUSIONS: Among various risk factors for thromboembolic events, it is reasonable to avoid a rapid increase and decline in hemoglobin levels as well as ensure TSAT ≥ 30%, rather than increasing the roxadustat dose. Graphical Abstract available for this article. TRIAL REGISTRATION: NCT02278341, NCT02273726, NCT02052310, NCT02174731.

Roxadustat is an oral treatment for patients with anemia, or low hemoglobin levels, due to chronic kidney disease. Thromboembolic events are caused by a blood clot blocking blood vessels, and they have occurred in clinical trials of roxadustat. This analysis evaluated risk factors for thromboembolic events in patients receiving roxadustat to treat anemia of chronic kidney disease who are on dialysis. Two different statistical approaches were used to investigate risk factors for thromboembolic events that occurred before and after 12 weeks of roxadustat treatment. We found that rapid improvement of anemia after starting roxadustat treatment may be associated with an increased risk of thromboembolic events occurring in the first 12 weeks of treatment. In contrast, severe anemia or worsening of anemia was associated with an increased risk of thromboembolic events after week 12. Low iron levels in the blood or greater decline of available iron in the blood from baseline were also detected as risk factors for the events after week 12, suggesting that iron supplementation is important in patients who are iron-deficient. Moreover, thromboembolic events were also associated with older age (≥ 65 years), Black race, high levels of inflammation, and having had a previous thromboembolic event or having a history of cardiovascular disease or diabetes. Some risk factors, such as iron status and hemoglobin levels, can be changed after beginning roxadustat treatment and should be monitored and modified, as needed.

Gaps in guideline-recommended anticoagulation in patients with atrial fibrillation and elevated thromboembolic risk within an integrated healthcare delivery system.

BACKGROUND: Atrial Fibrillation (AF) is the leading cause of stroke, which can be reduced by 70% with appropriate oral anticoagulation (OAC) therapy. Nationally, appropriate anticoagulation rates for patients with AF with elevated thromboembolic risk are as low as 50% even across the highest stroke risk cohorts. This study aims to evaluate the variability of appropriate anticoagulation rates among patients by sex, ethnicity, and socioeconomic status within the Kaiser Permanente Mid-Atlantic States (KPMAS). METHODS: This retrospective study investigated 9513 patients in KPMAS's AF registry with CHADS2 score ≥ 2 over a 6-month period in 2021. RESULTS: Appropriately anticoagulated patients had higher rates of diabetes, prior stroke, and congestive heart failure than patients who were not appropriately anticoagulated. There were no significant differences in anticoagulation rates between males and females (71.8% vs. 71.6%%, [OR] 1.01; 95% CI, 0.93-1.11; P = .76) nor by SES-SVI quartiles. There was a statistically significant difference between Black and White patients (70.8% vs. 73.1%, P = .03) and Asian and White patients (68.3% vs. 71.6%, P = .005). After adjusting for CHADS2, this difference persisted for Black and White participants with CHADS2 scores of ≤3 (62.6% vs. 70.6%, P < .001) and for Asian and White participants with CHADS2 scores > 5 (68.0% vs. 79.3%, P < .001). CONCLUSIONS: Black and Asian patients may have differing rates of appropriate anticoagulation when compared with White patients. Characterizing such disparities is the first step towards addressing treatment gaps in AF.

Thromboembolic and hemorrhagic complications in patients with prosthetic heart valves cared for in a tertiary care center. What have we learned?

BACKGROUND: Heart valve replacement surgery with mechanical or biological prostheses entails a risk of thromboembolism and bleeding complications. OBJECTIVE: To determine the complications related to complementary anticoagulation therapy and the probability of risk. METHODS: One-hundred and sixty-three patients who underwent heart valve replacement between 2002 and 2016 with either mechanical or biological prostheses, and who received vitamin K antagonists after hospital discharge, were studied. Anticoagulation therapy was categorized into optimal and non-optimal according to INR values prior to the development of complications. Patients with comorbidities and other risk factors for thrombosis and/or bleeding were excluded. RESULTS: In total, 68.7 % of patients received mechanical prostheses, and 31.3 %, biological prostheses (p ≤ 0.001); 25.2 % experienced the complications that motivated the study (p ≤ 0.001), which were hemorrhagic in 48.8 %, thromboembolic in 26.8 %, and of both types in 24.4 % (relative risk = 4.229). Among the patients with complications, 95.1 % received mechanical prostheses, and 4.9 %, biological (p = 0.005); non-optimal INR was identified in 49.7 % (p ≤ 0.001). CONCLUSIONS: Given the high risk of thromboembolic and hemorrhagic complications, valve prostheses must be carefully chosen, and care priorities should include prevention and follow-up, especially in those patients who require anticoagulation therapy.

ANTECEDENTES: El reemplazo valvular por prótesis mecánicas o biológicas implica riesgo de tromboembolismo y complicaciones hemorrágicas. OBJETIVO: Determinar las complicaciones relacionadas con la terapia de anticoagulación complementaria y la probabilidad de riesgo en pacientes portadores de prótesis valvulares del corazón. MÉTODOS: Se estudiaron 163 pacientes entre 2002 y 2016, portadores de prótesis mecánicas y biológicas, quienes recibieron antagonistas de la vitamina K posterior al egreso hospitalario. La terapia de anticoagulación se categorizó en óptima y no óptima conforme a los valores de INR previos a las complicaciones. Fueron excluidos los pacientes con comorbilidades y otros factores de riesgo de trombosis y/o sangrado. RESULTADOS: a 68.7 % de los pacientes se les colocó prótesis mecánica y a 31.3 %, biológica (p ≤ 0.001); 25.2 % presentó las complicaciones motivo de estudio (p ≤ 0.001), hemorrágicas en 48.8 %, tromboembólicas en 26.8 % y de ambos tipos en 24.4 % (riesgo relativo = 4.229); a 95.1 % de los pacientes con complicaciones se les colocó prótesis mecánica y a 4.9 %, biológica (p = 0.005); 49.7 % presentó INR no óptimo (p ≤ 0.001). CONCLUSIONES: Ante riesgo alto de complicaciones tromboembólicas y hemorrágicas, la elección de las prótesis valvulares, la prevención y el seguimiento son prioridades, principalmente en quienes requieren terapia de anticoagulación.

Stroke in Atrial Fibrillation and Other Atrial Dysrhythmias.

PURPOSE OF REVIEW: Atrial fibrillation (AF) is a major risk factor for systemic embolism and ischaemic stroke. Furthermore, AF-related strokes are associated with higher mortality, greater disability, longer hospital stays and lower rates of hospital discharge than strokes caused by other reasons. The aim of this review to summarise the existing evidence on the association of AF with ischemic stroke and provide insights on the pathophysiological mechanisms and the clinical management of patients with AF in order to reduce the burden of ischemic stroke. RECENT FINDINGS: Beyond Virchow's triad, several pathophysiological mechanisms associated with structural changes in the left atrium, which may precede the identification of AF, may contribute to the increased risk of arterial embolism in AF patients. Individualised thromboembolic risk stratification based on CHA2DS2-VASc score and clinically relevant biomarkers provides essential tool towards a personalised holistic approach in thromboembolism prevention. Anticoagulation remains the cornerstone of stroke prevention moving from vitamin K antagonists (VKA) to safer non-vitamin K direct oral anticoagulants in the majority of AF patients. Despite the efficacy and safety of oral anticoagulation, still the equilibrium between thrombosis and haemostasis in AF patients remains suboptimal and future directions in anticoagulation and cardiac intervention may provide novel treatment options in stroke prevention. This review summarises the pathophysiologic mechanisms of thromboembolism, aiming the current and potential future perspectives in stroke prevention in AF patients.

Mobile health-technology integrated care in secondary prevention atrial fibrillation patients: a post-hoc analysis from the mAFA-II randomized clinical trial.

AF patients with history of thromboembolic events are at higher risk of thromboembolic recurrences, despite appropriate antithrombotic treatment. We aimed to evaluate the effect of mobile health (mHealth) technology-implemented 'Atrial fibrillation Better Care' (ABC) pathway approach (mAFA intervention) in secondary prevention AF patients. The Mobile Health Technology for Improved Screening and Optimized Integrated Care in AF (mAFA-II) cluster randomized trial enrolled adult AF patients across 40 centers in China. The main outcome was the composite outcome of stroke or thromboembolism, all-cause death, and rehospitalization. Using Inverse Probability of Treatment Weighting (IPTW), we evaluated the effect of the mAFA intervention in patients with and without prior history of thromboembolic events (i.e., ischemic stroke or thromboembolism). Among the 3324 patients enrolled in the trial, 496 (14.9%, mean age: 75.1 ± 11.4 years, 35.9% females) had a previous episode of thromboembolic event. No significant interaction was observed for the effect of mAFA intervention in patients with vs. without history of thromboembolic events [Hazard ratio, (HR): 0.38, 95% confidence interval (CI):0.18-0.80 vs. HR 0.55, 95% CI 0.17-1.76, p for interaction = 0.587); however, a trend towards lower efficacy of mAFA intervention among AF patients in secondary prevention was observed for secondary outcomes, with significant interaction for bleeding events (p = 0.034) and the composite of cardiovascular events (p = 0.015). A mHealth-technology-implemented ABC pathway provided generally consistent reduction of the risk of primary outcome in both primary and secondary prevention AF patients. Secondary prevention patients may require further specific approaches to improve clinical outcomes such as bleeding and cardiovascular events.Trial registration: WHO International Clinical Trials Registry Platform (ICTRP) Registration number ChiCTR-OOC-17014138.

Effectiveness and Safety of Dabigatran in Atrial Fibrillation Patients with Severe Obesity: a Real-World Retrospective Cohort Study.

BACKGROUND: Direct oral anticoagulants such as dabigatran are the preferred anticoagulant in treating atrial fibrillation (AF) patients due to their effectiveness and safety. Whether this applies to severely obese patients needs to be determined. OBJECTIVE: To compare the effectiveness and safety of dabigatran with warfarin among AF patients with severe obesity. DESIGN: Retrospective cohort study. PARTICIPANTS: AF patients with a BMI >40kg/m2 or a weight >120kg receiving dabigatran or warfarin between 10/01/2010 and 12/31/2019 in a large integrated health system and followed through 08/01/2020. INTERVENTIONS: Not applicable. MAIN MEASURES: Primary effectiveness outcome was composite thromboembolism including transient ischemic attack, ischemic stroke, or systemic embolism. Primary safety outcome was composite bleeding including gastrointestinal bleeding, intracranial bleeding, or other bleeding. Secondary outcomes included the individual outcomes and all-cause mortality. Propensity score matching (PSM) was performed to create a 1:1 matched cohort and Cox proportional hazards model was used to estimate the hazard ratio (HR) of each outcome for dabigatran users compared to warfarin users. KEY RESULTS: A total of 6848 patients receiving either dabigatran or warfarin were identified. In a 1:1 matched cohort, dabigatran users had a HR of 0.71 (95% confidence interval (CI): 0.56-0.91) for composite thromboembolism, a HR of 1.24 (95%CI: 1.07-1.42) for composite bleeding, and a HR of 0.57 (95% CI: 0.45-0.71) for all-cause mortality when compared to warfarin users. CONCLUSIONS: Among AF patients with a BMI >40kg/m2 or a weight >120kg in a real-world clinical setting, dabigatran was effective in reducing the risk of thromboembolism and mortality but was associated with an increased risk of bleeding when compared to warfarin. Dabigatran may be a reasonable option for AF patients with severe obesity.

The Effects of Implementing a Mobile Health-Technology Supported Pathway on Atrial Fibrillation-Related Adverse Events Among Patients With Multimorbidity: The mAFA-II Randomized Clinical Trial.

Importance: The Mobile Health Technology for Improved Screening and Optimized Integrated Care in Atrial Fibrillation (mAFA-II) trial is a prospective cluster randomized trial that found a significant reduction in the composite clinical outcome of stroke or thromboembolism, all-cause death, and rehospitalization among patients with atrial fibrillation (AF) who used a mobile health (mHealth) technology that implemented the Atrial Fibrillation Better Care (ABC) pathway (ie, A, anticoagulation/avoid stroke; B, better symptom control; and C, cardiovascular disease and comorbidity management) compared with those receiving usual care. Multimorbidity (defined as ≥2 chronic long-term conditions) is common in older patients with AF, but the impact of integrated or holistic care (based on the ABC pathway) on clinical outcomes in this population is uncertain. Objective: To evaluate whether implementation of the integrated ABC pathway, supported by mHealth technology, would reduce AF-related adverse events in patients with multimorbidity. Design, Setting, and Participants: This prespecified ancillary analysis of data from the extended follow-up of the mAFA II trial was conducted between June 2018 and April 2021. Adult patients with AF were included in the analysis if they had at least 2 comorbidities. Participants were enrolled across 40 centers in China. Intervention: Integrated care supported by mHealth technology (mAFA intervention) vs usual care. Main Outcomes and Measures: The main outcome was the composite outcome of stroke or thromboembolism, all-cause death, and rehospitalization. Cox proportional hazard modeling was performed for adverse outcomes after adjusting for cluster effect and baseline risk factors. Results: Of 1890 patients, 833 (mean [SD] age, 72.0 [12.0] years; 278 [33.4%] women) with multimorbidity were allocated to the intervention group (ABC pathway), with a mean (SD) follow-up of 419 (257) days, and 1057 patients (mean [SD] age, 72.8 [13.0] years; 443 [41.9%] women) with multimorbidity were allocated to usual care, with a mean (SD) follow-up of 457 (154) days. Compared with usual care, the composite outcome of stroke or thromboembolism, all-cause death, and rehospitalization was significantly reduced in the intervention group (hazard ratio [HR], 0.37; 95% CI, 0.26-0.53; P < .001), as were rehospitalizations alone (HR, 0.42; 95% CI, 0.27-0.64; P < .001). For the C criterion of the ABC pathway, rates of acute coronary syndrome, heart failure, and uncontrolled blood pressure during follow-up were lower in the intervention group than the usual care group (27 patients [3.2%] vs 145 patients [13.7%]; HR, 0.29; 95% CI, 0.19-0.45; P < .001). Subgroup analyses by age, prior stroke, and sex demonstrated consistently lower HRs for the primary composite outcome and rehospitalization for patients with AF allocated to the intervention group compared with patients receiving usual care. Conclusions and Relevance: In this study, mHealth technology-based integrated care that facilitated the implementation of the ABC pathway reduced meaningful clinical adverse events in older patients with AF and multimorbidity vs usual care. Trial Registration: WHO International Clinical Trials Registry Platform (ICTRP) Registration number: ChiCTR-OOC-17014138.

Exploratory Evaluation of Rhythm Control by Dronedarone in Combination With Low-Dose Rivaroxaban, Warfarin, Antiplatelet, or None of the Antithrombotic Therapy in High-Risk Patients With Non-Permanent Atrial Fibrillation: A Retrospective Cohort Study.

The emerging data supports rhythm control to prevent major adverse cardiac events (MACE) in high-risk patients with atrial fibrillation (AF). Limited data demonstrated rivaroxaban 10 mg combining dronedarone seemed feasible. This study aimed at investigating clinical events in a dronedarone-treated cohort. This exploratory, retrospective chart review was conducted in nonpermanent AF patients receiving dronedarone for ≥ 3 months between 2009/1 and 2016/2. In Taiwan, dronedarone's labeled indication was strict to age ≥ 70 or 65 to 70 years with either hypertension, diabetes, prior stroke, or left atrium >50 mm. We divided all into 4 groups using antithrombotic strategies to evaluate the safety, effectiveness, and MACE endpoints. A total of 689 patients (mean CHA2DS2-VASc score 3.8 ± 1.4) were analyzed: rivaroxaban 10 mg (n = 93, 13.5%), warfarin (n = 89, 12.9%), antiplatelet (n = 331, 48.0%), and none (n = 176, 25.5%). During the follow-up period (mean 946 ± 493.8 days), the rivaroxaban group did not report any stroke or thromboembolism (ishcmeic stroke rate: antiplatelet [0.6%], none [1.1%]; hemorrahgic stroke rate: warfarin [2.2%]; thromboembolism rate: warfarin [2.2%]). There was no significant difference in safety, effectiveness, and MACE endpoints between groups. Also, >104 weeks of dronedarone use was the independent predictor for MACE after adjusting the strategy and other covariates (hazard ratio 0.14 [95% confidence interval 0.04-0.44], P = .001). Our findings warrant concomitant rivaroxaban 10 mg and dronedarone for further investigation. Regardless of antithrombotic strategies, a more extended persistence of dronedarone was associated with fewer MACE.

Medically Ill hospitalized Patients for COVID-19 THrombosis Extended ProphyLaxis with rivaroxaban ThErapy: Rationale and Design of the MICHELLE Trial.

BACKGROUND: The devastating Coronavirus disease (COVID-19) pandemic is associated with a high prothrombotic state. It is unclear if the coagulation abnormalities occur because of the direct effect of SARS-CoV-2 or indirectly by the cytokine storm and endothelial damage or by a combination of mechanisms. There is a clear indication of in-hospital pharmacological thromboprophylaxis for every patient with COVID-19 after bleed risk assessment. However, there is much debate regarding the best dosage regimen, and there is no consensus on the role of extended thromboprophylaxis. DESIGN: This study aims to evaluate the safety and efficacy of rivaroxaban 10 mg once daily for 35 ± 4 days versus no intervention after hospital discharge in COVID-19 patients who were at increased risk for VTE and have received standard parenteral VTE prophylaxis during hospitalization. The composite efficacy endpoint is a combination of symptomatic VTE, VTE-related death, VTE detected by bilateral lower limbs venous duplex scan and computed tomography pulmonary angiogram on day 35 ± 4 posthospital discharge and symptomatic arterial thromboembolism (myocardial infarction, nonhemorrhagic stroke, major adverse limb events, and cardiovascular death) up to day 35 ± 4 posthospital discharge. The key safety outcome is the incidence of major bleeding according to ISTH criteria. SUMMARY: The MICHELLE trial is expected to provide high-quality evidence around the role of extended thromboprophylaxis in COVID-19 and will help guide medical decisions in clinical practice.1.

Anticoagulation versus placebo for heart failure in sinus rhythm.

BACKGROUND: People with chronic heart failure (HF) are at risk of thromboembolic events, including stroke, pulmonary embolism, and peripheral arterial embolism; coronary ischaemic events also contribute to the progression of HF. The use of long-term oral anticoagulation is established in certain populations, including people with HF and atrial fibrillation (AF), but there is wide variation in the indications and use of oral anticoagulation in the broader HF population. OBJECTIVES: To determine whether long-term oral anticoagulation reduces total deaths and stroke in people with heart failure in sinus rhythm. SEARCH METHODS: We updated the searches in CENTRAL, MEDLINE, and Embase in March 2020. We screened reference lists of papers and abstracts from national and international cardiovascular meetings to identify unpublished studies. We contacted relevant authors to obtain further data. We did not apply any language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCT) comparing oral anticoagulants with placebo or no treatment in adults with HF, with treatment duration of at least one month. We made inclusion decisions in duplicate, and resolved any disagreements between review authors by discussion, or a third party. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, and assessed the risks and benefits of antithrombotic therapy by calculating odds ratio (OR), accompanied by the 95% confidence intervals (CI). MAIN RESULTS: We identified three RCTs (5498 participants). One RCT compared warfarin, aspirin, and no antithrombotic therapy, the second compared warfarin with placebo in participants with idiopathic dilated cardiomyopathy, and the third compared rivaroxaban with placebo in participants with HF and coronary artery disease. We pooled data from the studies that compared warfarin with a placebo or no treatment. We are uncertain if there is an effect on all-cause death (OR 0.66, 95% CI 0.36 to 1.18; 2 studies, 324 participants; low-certainty evidence); warfarin may increase the risk of major bleeding events (OR 5.98, 95% CI 1.71 to 20.93, NNTH 17). 2 studies, 324 participants; low-certainty evidence). None of the studies reported stroke as an individual outcome. Rivaroxaban makes little to no difference to all-cause death compared with placebo (OR 0.99, 95% CI 0.87 to 1.13; 1 study, 5022 participants; high-certainty evidence). Rivaroxaban probably reduces the risk of stroke compared to placebo (OR 0.67, 95% CI 0.47 to 0.95; NNTB 101; 1 study, 5022 participants; moderate-certainty evidence), and probably increases the risk of major bleeding events (OR 1.65, 95% CI 1.17 to 2.33; NNTH 79; 1 study, 5008 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Based on the three RCTs, there is no evidence that oral anticoagulant therapy modifies mortality in people with HF in sinus rhythm. The evidence is uncertain if warfarin has any effect on all-cause death compared to placebo or no treatment, but it may increase the risk of major bleeding events. There is no evidence of a difference in the effect of rivaroxaban on all-cause death compared to placebo. It probably reduces the risk of stroke, but probably increases the risk of major bleedings. The available evidence does not support the routine use of anticoagulation in people with HF who remain in sinus rhythm.

Appropriate intraprocedural initial heparin dosing in patients undergoing catheter ablation for atrial fibrillation receiving uninterrupted non-vitamin-K antagonist oral anticoagulant treatment.

BACKGROUND: To clarify the appropriate initial dosage of heparin during radiofrequency catheter ablation (RFCA) in patients with atrial fibrillation (AF) receiving uninterrupted nonvitamin K antagonist oral anticoagulant (NOAC) treatment. METHODS: A total of 187 consecutive AF patients who underwent their first RFCA in our center were included. In the warfarin group (WG), an initial heparin dose of 100 U/kg was administered (control group: n = 38). The patients who were on NOACs were randomly divided into 3 NOAC groups (NG: n = 149), NG110, NG120, and NG130, and were administered initial heparin doses of 110 U/kg, 120 U/kg, and 130 U/kg, respectively. During RFCA, the activated clotting time (ACT) was measured every 15 min, and the target ACT was maintained at 250-350 s by intermittent heparin infusion. The baseline ACT and ACTs at each 15-min interval, the average percentage of measurements at the target ACT, and the incidence of periprocedural bleeding and thromboembolic complications were recorded and analyzed. RESULTS: There was no significant difference in sex, age, weight, or baseline ACT among the four groups. The 15 min-ACT, 30 min-ACT, and 45 min-ACT were significantly longer in the WG than in NG110 and NG120. However, no significant difference in 60 min-ACT or 75 min-ACT was detected. The average percentages of measurements at the target ACT in NG120 (82.2 ± 23.6%) and NG130 (84.8 ± 23.7%) were remarkably higher than those in the WG (63.4 ± 36.2%, p = 0.007, 0.003, respectively). These differences were independent of the type of NOAC. The proportion of ACTs in 300-350 s in NG130 was higher than in WG (32.4 ± 31.8 vs. 34.7 ± 30.6, p = 0.735). Severe periprocedural thromboembolic and bleeding complications were not observed. CONCLUSIONS: For patients with AF receiving uninterrupted NOAC treatment who underwent RFCA, an initial heparin dosage of 120 U/kg or 130 U/kg can provide an adequate intraprocedural anticoagulant effect, and 130 U/kg allowed ACT to reach the target earlier. TRIAL REGISTRATION: Registration number: ChiCTR1800016491, First Registration Date: 04/06/2018 (Chinese Clinical Trial Registry http://www.chictr.org.cn/index.aspx ).

Comparative Effectiveness and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation Patients.

BACKGROUND AND PURPOSE: Several observational studies have compared the effect of the non-vitamin K antagonist oral anticoagulants to each other in patients with atrial fibrillation. However, confounding by indication is a major problem when comparing non-vitamin K antagonist oral anticoagulant treatments in some of these studies. This meta-analysis was conducted to compare the effectiveness and safety between non-vitamin K antagonist oral anticoagulant and non-vitamin K antagonist oral anticoagulant by only including the propensity score matching studies. METHODS: We systematically searched the PubMed and Ovid databases until May 2020 to identify relevant observational studies. Hazard ratios (HRs) and 95% CIs of the reported outcomes were collected and then pooled by a random-effects model complemented with an inverse variance heterogeneity or quality effects model. RESULTS: A total of 17 retrospective cohort studies were included in this meta-analysis. Compared with dabigatran use, the use of rivaroxaban was significantly associated with increased risks of stroke or systemic embolism (HR, 1.16 [95% CI, 1.05-1.29]) and major bleeding (HR, 1.32 [95% CI, 1.24-1.41]), whereas the use of apixaban was associated with a reduced risk of major bleeding (HR, 0.78 [95% CI, 0.67-0.90]) but not stroke or systemic embolism (HR, 0.84 [95% CI, 0.56-1.28]). Compared with rivaroxaban use, the use of apixaban was associated with a decreased risk of major bleeding (HR, 0.63 [95% CI, 0.54-0.73]) but not stroke or systemic embolism (HR, 0.83 [95% CI, 0.67-1.04]). Reanalyses with the inverse variance heterogeneity or quality effects model produced similar results as the random-effects model. CONCLUSIONS: Current observational comparisons with propensity score matching methods suggest that apixaban might be a better choice compared with dabigatran or rivaroxaban for stroke prevention in atrial fibrillation patients.

AhR and IDO1 in pathogenesis of Covid-19 and the "Systemic AhR Activation Syndrome:" a translational review and therapeutic perspectives.

Covid-19 is the acute illness caused by SARS-CoV-2 with initial clinical symptoms such as cough, fever, malaise, headache, and anosmia. After entry into cells, corona viruses (CoV) activate aryl hydrocarbon receptors (AhRs) by an indoleamine 2,3-dioxygenase (IDO1)-independent mechanism, bypassing the IDO1-kynurenine-AhR pathway. The IDO1-kynurenine-AhR signaling pathway is used by multiple viral, microbial and parasitic pathogens to activate AhRs and to establish infections. AhRs enhance their own activity through an IDO1-AhR-IDO1 positive feedback loop prolonging activation induced by pathogens. Direct activation of AhRs by CoV induces immediate and simultaneous up-regulation of diverse AhR-dependent downstream effectors, and this, in turn, results in a "Systemic AhR Activation Syndrome" (SAAS) consisting of inflammation, thromboembolism, and fibrosis, culminating in multiple organ injuries, and death. Activation of AhRs by CoV may lead to diverse sets of phenotypic disease pictures depending on time after infection, overall state of health, hormonal balance, age, gender, comorbidities, but also diet and environmental factors modulating AhRs. We hypothesize that elimination of factors known to up-regulate AhRs, or implementation of measures known to down-regulate AhRs, should decrease severity of infection. Although therapies selectively down-regulating both AhR and IDO1 are currently lacking, medications in clinical use such as dexamethasone may down-regulate both AhR and IDO1 genes, as calcitriol/vitamin D3 may down-regulate the AhR gene, and tocopherol/vitamin E may down-regulate the IDO1 gene. Supplementation of calcitriol should therefore be subjected to epidemiological studies and tested in prospective trials for prevention of CoV infections, as should tocopherol, whereas dexamethasone could be tried in interventional trials. Because lack of physical exercise activates AhRs via the IDO1-kynurenine-AhR signaling pathway increasing risk of infection, physical exercise should be encouraged during quarantines and stay-at-home orders during pandemic outbreaks. Understanding which factors affect gene expression of both AhR and IDO1 may help in designing therapies to prevent and treat humans suffering from Covid-19.

Comparison of Different Anticoagulation Regimens Regarding Maternal and Fetal Outcomes in Pregnant Patients With Mechanical Prosthetic Heart Valves (from the Multicenter ANATOLIA-PREG Registry).

Mechanical prosthetic heart valves (MPHVs) are highly thrombogenic, and a pregnancy-induced procoagulant status increases the risk of MPHV thrombosis. Despite numerous case reports, 2 major registries and meta-analyses/systematic reviews, optimal anticoagulation therapy during pregnancy remains controversial. The goal of this study was to evaluate different anticoagulation regimens in pregnant patients with MPHVs. The outcomes of anticoagulation regimens were assessed retrospectively in pregnant women (110 women; 155 pregnancies) with MPHVs. The study population was divided into 5 groups according to anticoagulation regimens used; high-dose warfarin (>5 mg/d) throughout pregnancy (group 1), low-dose warfarin (≤5 mg/d) throughout pregnancy (group 2), low molecular weight heparin (LMWH) throughout pregnancy (group 3), first trimester LMWH, 2nd and 3rd trimester warfarin (group 4), first 2 trimester LMWH, and 3rd trimester warfarin (group 5). Of 155 pregnancies, 55 (35%) resulted in fetal loss; whereas 41 (27%) cases with abortion (miscarriage and therapeutic) and 14 (9%) stillbirths occurred. The comparison of the groups showed that the whole abortion rates including therapeutic abortion were significantly higher in Group 1, and lower in groups 3 and 5 (p <0.001). However, miscarriage rates were similar between the groups. A total of 53 pregnancies (34%) suffered from prosthetic valves thrombosis (PVT) during pregnancy or in the postpartum period. Group 2 had significantly lower rates of PVT than the other groups (p <0.001). In conclusion, the current data suggests that there is no optimal therapy, and that all managements have advantages and disadvantages. Low-dose warfarin (≤5 mg/day) regimen with therapeutic international normalized ratio levels may provide effective maternal protection throughout pregnancy with acceptable fetal outcomes.

Mobile Health Technology to Improve Care for Patients With Atrial Fibrillation.

BACKGROUND: Current management of patients with atrial fibrillation (AF) is limited by low detection of AF, non-adherence to guidelines, and lack of consideration of patients' preferences, thus highlighting the need for a more holistic and integrated approach to AF management. OBJECTIVE: The objective of this study was to determine whether a mobile health (mHealth) technology-supported AF integrated management strategy would reduce AF-related adverse events, compared with usual care. METHODS: This is a cluster randomized trial of patients with AF older than 18 years of age who were enrolled in 40 cities in China. Recruitment began on June 1, 2018 and follow-up ended on August 16, 2019. Patients with AF were randomized to receive usual care, or integrated care based on a mobile AF Application (mAFA) incorporating the ABC (Atrial Fibrillation Better Care) Pathway: A, Avoid stroke; B, Better symptom management; and C, Cardiovascular and other comorbidity risk reduction. The primary composite outcome was a composite of stroke/thromboembolism, all-cause death, and rehospitalization. Rehospitalization alone was a secondary outcome. Cardiovascular events were assessed using Cox proportional hazard modeling after adjusting for baseline risk. RESULTS: There were 1,646 patients allocated to mAFA intervention (mean age, 67.0 years; 38.0% female) with mean follow-up of 262 days, whereas 1,678 patients were allocated to usual care (mean age, 70.0 years; 38.0% female) with mean follow-up of 291 days. Rates of the composite outcome of 'ischemic stroke/systemic thromboembolism, death, and rehospitalization' were lower with the mAFA intervention compared with usual care (1.9% vs. 6.0%; hazard ratio [HR]: 0.39; 95% confidence interval [CI]: 0.22 to 0.67; p < 0.001). Rates of rehospitalization were lower with the mAFA intervention (1.2% vs. 4.5%; HR: 0.32; 95% CI: 0.17 to 0.60; p < 0.001). Subgroup analyses by sex, age, AF type, risk score, and comorbidities demonstrated consistently lower HRs for the composite outcome for patients receiving the mAFA intervention compared with usual care (all p < 0.05). CONCLUSIONS: An integrated care approach to holistic AF care, supported by mHealth technology, reduces the risks of rehospitalization and clinical adverse events. (Mobile Health [mHealth] technology integrating atrial fibrillation screening and ABC management approach trial; ChiCTR-OOC-17014138).

Omega-3 and hemocompatibility-related adverse events.

BACKGROUND: Hemocompatibility-related clinical adverse events (HRAEs) are major causes of readmission in patients with left ventricular assist devices (LVADs). Omega-3 is an unsaturated fatty acid that possesses anti-inflammatory and antiangiogenic properties. We aimed to investigate the impact of omega-3 therapy on HRAEs during LVAD support. METHODS: Consecutive LVAD patients who were followed for 6 months were enrolled, and stratified by the use of omega-3. Freedom from any HRAEs and net burden of HRAEs, which was calculated by using a hemocompatibility score (using 4 escalating tiers of hierarchal severity to derive a total score for events), were compared between those with and without omega-3 therapy. RESULTS: Among 169 LVAD patients (57 years old and 124 males), 31 patients received 4 g/d of omega-3 therapy and 138 patients were in the control group. During the 6-month observational period, freedom from any HRAEs was 90% in the omega-3 group compared with 70% in the control group with a hazard ratio of 0.35 (95% confidence interval 0.11-0.87 and P = .042). The average hemocompatibility score in the omega-3 group was significantly lower compared with the control group (0.23 vs 0.91; P = .042), due to reduced Tier I scores (mild HRAE; P = .003) and Tier IIIB scores (severe HRAE; P < .001). The similar trends remained at propensity-matched populations. CONCLUSIONS: Omega-3 therapy was associated with reduced HRAEs including both bleeding and thromboembolic events in LVAD patients.

Use of rivaroxaban in patients attending a hematology unit in clinical practice.

Aim: To determine drug persistence and rates of events among patients treated with rivaroxaban in a hematology unit. Methods: Retrospective study of patients that started treatment with rivaroxaban, in the hematology unit of a tertiary hospital. Results: A total of 161 patients were included, of whom 83.9% had atrial fibrillation and 11.2% venous thromboembolism, and 76.4% of patients were taking rivaroxaban 20 mg, 22.4% 15 mg and 1.2% 10 mg. After a follow-up of 1.8 ± 1.1 years, only four patients (2.5%) discontinued treatment. Rates of thromboembolic events, major bleeding/clinically relevant nonmajor bleeding and intracranial hemorrhage were 1.1, 2.8, 0.3 events per 100 patient-years, respectively. Conclusion: In patients attended in a hematology unit, medication persistence was high, and the incidence of outcomes low.