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Cardiovascular Research Feb 2022The prothrombotic state in atrial fibrillation (AF) occurs as a result of multifaceted interactions, known as Virchow's triad of hypercoagulability, structural... (Review)
Review
The prothrombotic state in atrial fibrillation (AF) occurs as a result of multifaceted interactions, known as Virchow's triad of hypercoagulability, structural abnormalities, and blood stasis. More recently, there is emerging evidence that lipoproteins are implicated in this process, beyond their traditional role in atherosclerosis. In this review, we provide an overview of the various lipoproteins and explore the association between lipoproteins and AF, the effects of lipoproteins on haemostasis, and the potential contribution of lipoproteins to thrombogenesis in AF. There are several types of lipoproteins based on size, lipid composition, and apolipoprotein category, namely: chylomicrons, very low-density lipoprotein, low-density lipoprotein (LDL), intermediate-density lipoprotein, and high-density lipoprotein. Each of these lipoproteins may contain numerous lipid species and proteins with a variety of different functions. Furthermore, the lipoprotein particles may be oxidized causing an alteration in their structure and content. Of note, there is a paradoxical inverse relationship between total cholesterol and LDL cholesterol (LDL-C) levels, and incident AF. The mechanism by which this occurs may be related to the stabilizing effect of cholesterol on myocardial membranes, along with its role in inflammation. Overall, specific lipoproteins may interact with haemostatic pathways to promote excess platelet activation and thrombin generation, as well as inhibiting fibrinolysis. In this regard, LDL-C has been shown to be an independent risk factor for thromboembolic events in AF. The complex relationship between lipoproteins, thrombosis and AF warrants further research with an aim to improve our knowledge base and contribute to our overall understanding of lipoprotein-mediated thrombosis.
Topics: Atrial Fibrillation; Cholesterol, LDL; Humans; Lipoproteins; Lipoproteins, HDL; Lipoproteins, LDL; Thrombosis
PubMed: 33483737
DOI: 10.1093/cvr/cvab017 -
Circulation Mar 2023Andexanet alfa is a modified recombinant inactive factor Xa (FXa) designed to reverse FXa inhibitors. ANNEXA-4 (Andexanet Alfa, a Novel Antidote to the Anticoagulation...
BACKGROUND
Andexanet alfa is a modified recombinant inactive factor Xa (FXa) designed to reverse FXa inhibitors. ANNEXA-4 (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) was a multicenter, prospective, phase-3b/4, single-group cohort study that evaluated andexanet alfa in patients with acute major bleeding. The results of the final analyses are presented.
METHODS
Patients with acute major bleeding within 18 hours of FXa inhibitor administration were enrolled. Co-primary end points were anti-FXa activity change from baseline during andexanet alfa treatment and excellent or good hemostatic efficacy, defined by a scale used in previous reversal studies, at 12 hours. The efficacy population included patients with baseline anti-FXa activity levels above predefined thresholds (≥75 ng/mL for apixaban and rivaroxaban, ≥40 ng/mL for edoxaban, and ≥0.25 IU/mL for enoxaparin; reported in the same units used for calibrators) who were adjudicated as meeting major bleeding criteria (modified International Society on Thrombosis and Haemostasis definition). The safety population included all patients. Major bleeding criteria, hemostatic efficacy, thrombotic events (stratified by occurring before or after restart of either prophylactic [ie, a lower dose, for prevention rather than treatment] or full-dose oral anticoagulation), and deaths were assessed by an independent adjudication committee. Median endogenous thrombin potential at baseline and across the follow-up period was a secondary outcome.
RESULTS
There were 479 patients enrolled (mean age, 78 years; 54% male; 86% White); 81% were anticoagulated for atrial fibrillation, and the median time was 11.4 hours since last dose, with 245 (51%) on apixaban, 176 (37%) on rivaroxaban, 36 (8%) on edoxaban, and 22 (5%) on enoxaparin. Bleeding was predominantly intracranial (n=331 [69%]) or gastrointestinal (n=109 [23%]). In evaluable apixaban patients (n=172), median anti-FXa activity decreased from 146.9 ng/mL to 10.0 ng/mL (reduction, 93% [95% CI, 94-93]); in rivaroxaban patients (n=132), it decreased from 214.6 ng/mL to 10.8 ng/mL (94% [95% CI, 95-93]); in edoxaban patients (n=28), it decreased from 121.1 ng/mL to 24.4 ng/mL (71% [95% CI, 82-65); and in enoxaparin patients (n=17), it decreased from 0.48 IU/mL to 0.11 IU/mL (75% [95% CI, 79-67]). Excellent or good hemostasis occurred in 274 of 342 evaluable patients (80% [95% CI, 75-84]). In the safety population, thrombotic events occurred in 50 (10%) patients; in 16 patients, these occurred during treatment with prophylactic anticoagulation that began after the bleeding event. No thrombotic episodes occurred after oral anticoagulation restart. Specific to certain populations, reduction of anti-FXa activity from baseline to nadir significantly predicted hemostatic efficacy in patients with intracranial hemorrhage (area under the receiver operating characteristic curve, 0.62 [95% CI, 0.54-0.70]) and correlated with lower mortality in patients <75 years of age (adjusted =0.022; unadjusted =0.003). Median endogenous thrombin potential was within the normal range by the end of andexanet alfa bolus through 24 hours for all FXa inhibitors.
CONCLUSIONS
In patients with major bleeding associated with the use of FXa inhibitors, treatment with andexanet alfa reduced anti-FXa activity and was associated with good or excellent hemostatic efficacy in 80% of patients.
REGISTRATION
URL: https://www.
CLINICALTRIALS
gov; Unique identifier: NCT02329327.
Topics: Aged; Female; Humans; Male; Anticoagulants; Cohort Studies; Enoxaparin; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Hemostatics; Prospective Studies; Recombinant Proteins; Rivaroxaban; Thrombin; Thrombosis
PubMed: 36802876
DOI: 10.1161/CIRCULATIONAHA.121.057844 -
American Journal of Physiology. Heart... Jan 2021The population suffering from coronary heart disease (CHD) complicated by atrial fibrillation (AF) is rising rapidly. A strong correlation between the two diseases has... (Review)
Review
The population suffering from coronary heart disease (CHD) complicated by atrial fibrillation (AF) is rising rapidly. A strong correlation between the two diseases has been reported, and the many common risk factors they share may play prominent roles in their development. In addition, CHD can directly promote the progression of AF by affecting reentry formation, focal ectopic activity, and neural remodeling. At the same time, AF also affects CHD through three aspects: ) atherosclerosis, ) the mismatch of blood supply and oxygen consumption, and ) thrombosis. In conclusion, CHD and AF can aggravate each other and seem to form a vicious cycle. For patients with CHD complicated by AF, principal studies and guidelines have focused on antithrombotic treatment and rhythm control, which are paramount for these patients. Of note, our review sheds light on the strategies to break the cycle of the two diseases, which may be fundamental to treat these patients and optimize the benefit.
Topics: Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Coronary Disease; Fibrinolytic Agents; Humans; Primary Prevention; Risk Assessment; Risk Factors; Secondary Prevention; Thrombosis
PubMed: 33185113
DOI: 10.1152/ajpheart.00702.2020 -
Annals of Internal Medicine Jan 2023Direct oral anticoagulants (DOACs) offer an alternative to low-molecular-weight heparin (LMWH) and warfarin for treating cancer-associated thrombosis (CAT). (Meta-Analysis)
Meta-Analysis
BACKGROUND
Direct oral anticoagulants (DOACs) offer an alternative to low-molecular-weight heparin (LMWH) and warfarin for treating cancer-associated thrombosis (CAT).
OBJECTIVE
To determine the cost and effectiveness of DOACs versus LMWH.
DESIGN
Cohort-state transition decision analytic model.
DATA SOURCES
Network meta-analysis comparing DOACs versus LMWH.
TARGET POPULATION
Adult patients with cancer at the time they develop thrombosis.
TIME HORIZON
Lifetime.
PERSPECTIVE
Health care sector.
INTERVENTION
Strategies of 1) enoxaparin, 2) apixaban, 3) edoxaban, and 4) rivaroxaban for treatment of CAT.
OUTCOME MEASURES
Incremental cost-effectiveness ratio (ICER) in 2022 U.S. dollars per quality-adjusted life-year (QALY) gained.
RESULTS OF BASE-CASE ANALYSIS
In the base-case scenario, using drug prices from the U.S. Department of Veterans Affairs Federal Supply Schedule, apixaban dominated enoxaparin and edoxaban by being less costly and more effective. Rivaroxaban was slightly more effective than apixaban, with an ICER of $493 246. In a scenario analysis using "real-world" drug prices from GoodRx, rivaroxaban was cost-effective with an ICER of $50 053 per QALY.
RESULTS OF SENSITIVITY ANALYSIS
Results were highly sensitive to monthly drug costs. Probabilistic sensitivity analyses showed that at a willingness-to-pay threshold of $50 000 per QALY, apixaban was preferred in 80% of simulations. However, sensitivity analyses also demonstrated that apixaban only remained cost-effective if monthly medication costs were below $530. Above this, rivaroxaban became cost-effective.
LIMITATIONS
An assumption was made that patients would continue anticoagulation indefinitely unless they suffered a major bleed. Nonmedical costs such as patient and caregiver loss of productivity were not accounted for, and long-term thrombotic complications were not explicitly modeled.
CONCLUSION
The 3 DOACs are more effective and more cost-effective than LMWH. The most cost-effective DOAC depends on the relative cost of each of these agents. These are important considerations for treating physicians and health policymakers.
PRIMARY FUNDING SOURCE
None.
Topics: Humans; Rivaroxaban; Heparin, Low-Molecular-Weight; Enoxaparin; Cost-Effectiveness Analysis; Cost-Benefit Analysis; Anticoagulants; Thrombosis; Neoplasms; Quality-Adjusted Life Years; Atrial Fibrillation
PubMed: 36571839
DOI: 10.7326/M22-1258 -
JAMA Cardiology Aug 2022Appropriate regimens of antithrombotic therapy for patients with atrial fibrillation (AF) and coronary artery disease (CAD) have not yet been established. (Randomized Controlled Trial)
Randomized Controlled Trial
Rivaroxaban Monotherapy vs Combination Therapy With Antiplatelets on Total Thrombotic and Bleeding Events in Atrial Fibrillation With Stable Coronary Artery Disease: A Post Hoc Secondary Analysis of the AFIRE Trial.
IMPORTANCE
Appropriate regimens of antithrombotic therapy for patients with atrial fibrillation (AF) and coronary artery disease (CAD) have not yet been established.
OBJECTIVE
To compare the total number of thrombotic and/or bleeding events between rivaroxaban monotherapy and combined rivaroxaban and antiplatelet therapy in such patients.
DESIGN, SETTING, AND PARTICIPANTS
This was a post hoc secondary analysis of the Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease (AFIRE) open-label, randomized clinical trial. This multicenter analysis was conducted from February 23, 2015, to July 31, 2018. Patients with AF and stable CAD who had undergone percutaneous coronary intervention or coronary artery bypass grafting 1 or more years earlier or who had angiographically confirmed CAD not requiring revascularization were enrolled. Data were analyzed from September 1, 2020, to March 26, 2021.
INTERVENTIONS
Rivaroxaban monotherapy or combined rivaroxaban and antiplatelet therapy.
MAIN OUTCOMES AND MEASURES
The total incidence of thrombotic, bleeding, and fatal events was compared between the groups. Cox regression analyses were used to estimate the risk of subsequent events in the 2 groups, with the status of thrombotic or bleeding events that had occurred by the time of death used as a time-dependent variable.
RESULTS
A total of 2215 patients (mean [SD] age, 74 [8.2] years; 1751 men [79.1%]) were included in the modified intention-to-treat analysis. The total event rates for the rivaroxaban monotherapy group (1107 [50.0%]) and the combination-therapy group (1108 [50.0%]) were 12.2% (135 of 1107) and 19.2% (213 of 1108), respectively, during a median follow-up of 24.1 (IQR, 17.3-31.5) months. The mortality rate was 3.7% (41 of 1107) in the monotherapy group and 6.6% (73 of 1108) in the combination-therapy group. Rivaroxaban monotherapy was associated with a lower risk of total events compared with combination therapy (hazard ratio, 0.62; 95% CI, 0.48-0.80; P < .001). Monotherapy was an independent factor associated with a lower risk of subsequent events compared with combination therapy. The mortality risk after a bleeding event (monotherapy, 75% [6 of 8]; combination therapy, 62.1% [18 of 29]) was higher than that after a thrombotic event (monotherapy, 25% [2 of 8]; combination therapy, 37.9% [11 of 29]).
CONCLUSIONS AND RELEVANCE
Rivaroxaban monotherapy was associated with lower risks of total thrombotic and/or bleeding events than combination therapy in patients with AF and stable CAD. Tapered antithrombotic therapy with a sole anticoagulant should be considered in these patients.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02642419.
Topics: Aged; Atrial Fibrillation; Coronary Artery Disease; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Humans; Male; Platelet Aggregation Inhibitors; Rivaroxaban; Thrombosis
PubMed: 35704345
DOI: 10.1001/jamacardio.2022.1561 -
Journal of Hepatology Dec 2023Historically, anticoagulants were contraindicated in patients with cirrhosis owing to concerns about bleeding risks. However, recent studies have shown that patients... (Review)
Review
Historically, anticoagulants were contraindicated in patients with cirrhosis owing to concerns about bleeding risks. However, recent studies have shown that patients with cirrhosis are not naturally anticoagulated and are at increased risk of prothrombotic events, such as portal venous thrombosis. In this article, we review preclinical and clinical data on the effects of anticoagulants in cirrhosis, including their potential benefits in reducing liver fibrosis, portal hypertension, and improving survival. Despite promising preclinical evidence, clinical translation has proven challenging. Nevertheless, we discuss the use of anticoagulation in specific clinical scenarios, such as patients with atrial fibrillation and portal vein thrombosis, and highlight the need for further research, including randomised-controlled trials, to determine the optimal role of anticoagulants in the management of patients with cirrhosis.
Topics: Humans; Anticoagulants; Portal Vein; Evidence Gaps; Liver Cirrhosis; Venous Thrombosis
PubMed: 37302580
DOI: 10.1016/j.jhep.2023.06.001 -
Archives of Cardiovascular Diseases Oct 2020
Topics: Atrial Appendage; Heart Atria; Heart Diseases; Humans; Thrombosis
PubMed: 32958416
DOI: 10.1016/j.acvd.2020.08.001 -
JACC. Cardiovascular Interventions Nov 2021This study evaluated the long-term efficacy of a standard antithrombotic strategy versus half-dose direct oral anticoagulation (DOAC) after Watchman implantation.
OBJECTIVES
This study evaluated the long-term efficacy of a standard antithrombotic strategy versus half-dose direct oral anticoagulation (DOAC) after Watchman implantation.
BACKGROUND
No consensus currently exists on the selection of the most effective antithrombotic strategy to prevent device-related thrombosis (DRT) in patients undergoing endocardial left atrial appendage closure.
METHODS
After successful left atrial appendage closure, consecutive patients were prescribed a standard antithrombotic strategy (SAT) or long-term half-dose DOAC (hdDOAC). The primary composite endpoint was DRT and thromboembolic (TE) and bleeding events.
RESULTS
Overall, 555 patients (mean age 75 ± 8 years, 63% male; median CHADS-VASc [congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age 65-74 years, sex category] score 4 [interquartile range (IQR): 3-6]; median HAS-BLED [hypertension, abnormal renal or liver function, stroke, bleeding, labile international normalized ratio, elderly, drugs or alcohol] score 3 [IQR: 2-4]) were included. Patients were categorized into 2 groups (SAT: n = 357 vs hdDOAC: n = 198). Baseline clinical characteristics were similar between groups. The median follow-up duration was 13 months (IQR: 12-15 months). DRT occurred in 12 (2.1%) patients, all in the SAT group (3.4% vs 0.0%; log-rank P = 0.009). The risk of nonprocedural major bleeding was significantly more favorable in the hdDOAC group (0.5% vs. 3.9%; log-rank P = 0.018). The rate of the primary composite endpoint of DRT and TE and major bleeding events was 9.5% in SAT patients and 1.0% in hdDOAC patients (HR: 9.8; 95% CI: 2.3-40.7; P = 0.002).
CONCLUSIONS
After successful Watchman implantation, long-term half-dose DOAC significantly reduced the risk of the composite endpoint of DRT and TE and major bleeding events compared with a standard, antiplatelet-based, antithrombotic therapy.
Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Appendage; Atrial Fibrillation; Female; Fibrinolytic Agents; Humans; Male; Stroke; Treatment Outcome
PubMed: 34656496
DOI: 10.1016/j.jcin.2021.07.031 -
Medical Ultrasonography Mar 2023
Topics: Humans; Atrial Fibrillation; Thrombosis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Heart Atria
PubMed: 36996396
DOI: 10.11152/mu-4017 -
Clinical and Translational Medicine Jun 2023Atrial fibrillation (AF) is associated with an increased risk of thrombosis of the left atrial appendage (LAA). However, the molecular mechanisms underlying this...
BACKGROUND
Atrial fibrillation (AF) is associated with an increased risk of thrombosis of the left atrial appendage (LAA). However, the molecular mechanisms underlying this site-specificity remain poorly understood. Here, we present a comparative single-cell transcriptional profile of paired atrial appendages from patients with AF and illustrate the chamber-specific properties of the main cell types.
METHODS
Single-cell RNA sequencing analysis of matched atrial appendage samples from three patients with persistent AF was evaluated by 10× genomics. The AF mice model was created using Tbx5 knockout mice. Validation experiments were performed by glutathione S-transferase pull-down assays, coimmunoprecipitation (Co-IP), cleavage assays and shear stress experiments in vitro.
RESULTS
In LAA, phenotype switching from endothelial cells to fibroblasts and inflammation associated with proinflammatory macrophage infiltration were observed. Importantly, the coagulation cascade is highly enriched in LAA endocardial endothelial cells (EECs), accompanying the up-regulation of a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) and the down-regulation of the tissue factor pathway inhibitor (TFPI) and TFPI2. Similar alterations were verified in an AF mouse model (Tbx5 ) and EECs treated with simulated AF shear stress in vitro. Furthermore, we revealed that the cleavage of both TFPI and TFPI2 based on their interaction with ADAMTS1 would lead to loss of anticoagulant activities of EECs.
CONCLUSIONS
This study highlights the decrease in the anticoagulant status of EECs in LAA as a potential mechanism underlying the propensity for thrombosis, which may aid the development of anticoagulation therapeutic approaches targeting functionally distinct cell subsets or molecules during AF.
Topics: Animals; Mice; Atrial Fibrillation; Atrial Appendage; Endothelial Cells; Thrombosis; Anticoagulants; Sequence Analysis, RNA
PubMed: 37278111
DOI: 10.1002/ctm2.1297