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Open Heart Jul 2024The extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once...
BACKGROUND
The extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial (ROCKET) atrial fibrillation (AF)-the landmark trials for the approval of apixaban and rivaroxaban, respectively, for non-valvular AF-were influenced by differences in their protocols is debated. The potential influence of selection criteria on trial results was assessed by emulating these trials in data from the Global Anticoagulant Registry in the Field (GARFIELD)-AF registry.
METHODS
Vitamin K antagonist (VKA) and non-vitamin K oral antagonist (NOAC) users from GARFIELD-AF were selected according to eligibility for the original ARISTOTLE or ROCKET AF trials. A propensity score overlap weighted Cox model was used to emulate trial randomisation between treatment groups. Adjusted HRs for stroke or systemic embolism (SE) within 2 years of enrolment were calculated for each NOAC versus VKA.
RESULTS
Among patients on apixaban, rivaroxaban and VKA, 2570, 3560 and 8005 were eligible for ARISTOTLE, respectively, and 1612, 2005 and 4368, respectively, for ROCKET AF. When selecting for ARISTOTLE criteria, apixaban users had significantly lower stroke/SE risk versus VKA (HR 0.57; 95% CI 0.34 to 0.94) while no reduction was observed with rivaroxaban (HR 0.98; 95% CI 0.68 to 1.40). When selecting for ROCKET AF criteria, safety and efficacy versus VKA were similar across the NOACs.
CONCLUSION
Apixaban and rivaroxaban showed similar results versus VKA in high-risk patients selected according to ROCKET AF criteria, whereas differences emerged when selecting for the more inclusive ARISTOTLE criteria. Our results highlight the importance of trial selection criteria in interpreting trial results and underline the problems faced in comparing treatments across rather than within clinical trials.
Topics: Humans; Atrial Fibrillation; Factor Xa Inhibitors; Patient Selection; Stroke; Pyrazoles; Pyridones; Rivaroxaban; Male; Female; Aged; Treatment Outcome; Registries; Administration, Oral; Risk Factors; Randomized Controlled Trials as Topic; Risk Assessment; Anticoagulants; Vitamin K
PubMed: 38955399
DOI: 10.1136/openhrt-2024-002708 -
Scientific Reports Jun 2024Subclinical leaflet thrombosis (SLT) can be one of the causes of transcatheter heart valve (THV) failure after transcatheter aortic valve implantation (TAVI). We sought...
Subclinical leaflet thrombosis (SLT) can be one of the causes of transcatheter heart valve (THV) failure after transcatheter aortic valve implantation (TAVI). We sought to clarify the formation process of SLT and thrombogenicity during the perioperative period of TAVI. This multicenter, prospective, single-arm interventional study enrolled 26 patients treated with edoxaban for atrial fibrillation and who underwent TAVI for severe aortic stenosis between September 2018 and September 2022. We investigated changes in maximal leaflet thickness detected by contrast-enhanced computed tomography between 1 week and 3 months after TAVI in 18 patients and measured the thrombogenicity by Total Thrombus-formation Analysis System (T-TAS) and flow stagnation volume by computational fluid dynamics (CFD) (n = 11). SLT was observed in 16.7% (3/18) at 1 week, but decreased to 5.9% (1/17) at 3 months after TAVI. Patients with SLT at 1 week had a significantly decreased maximal leaflet thickness compared to those without SLT. Thrombogenicity assessed by T-TAS decreased markedly at 1 week and tended to increase at 3 months. The stagnation volume assessed by CFD was positively associated with a higher maximum leaflet thickness. This study showed the course of leaflet thrombus formation and visualization of stagnation in neo-sinus of THV in the acute phase after TAVI.
Topics: Humans; Aortic Valve Stenosis; Transcatheter Aortic Valve Replacement; Atrial Fibrillation; Thrombosis; Female; Male; Aged, 80 and over; Aged; Prospective Studies; Aortic Valve; Severity of Illness Index; Pyridines; Thiazoles
PubMed: 38942790
DOI: 10.1038/s41598-024-65600-5 -
Biomolecules Jun 2024Antithrombin (AT) is a critical regulator of the coagulation cascade by inhibiting multiple coagulation factors including thrombin and FXa. Binding of heparinoids to...
Molecular Mechanisms of the Impaired Heparin Pentasaccharide Interactions in 10 Antithrombin Heparin Binding Site Mutants Revealed by Enhanced Sampling Molecular Dynamics.
Antithrombin (AT) is a critical regulator of the coagulation cascade by inhibiting multiple coagulation factors including thrombin and FXa. Binding of heparinoids to this serpin enhances the inhibition considerably. Mutations located in the heparin binding site of AT result in thrombophilia in affected individuals. Our aim was to study 10 antithrombin mutations known to affect their heparin binding in a heparin pentasaccharide bound state using two molecular dynamics (MD) based methods providing enhanced sampling, GaMD and LiGaMD2. The latter provides an additional boost to the ligand and the most important binding site residues. From our GaMD simulations we were able to identify four variants (three affecting amino acid Arg47 and one affecting Lys114) that have a particularly large effect on binding. The additional acceleration provided by LiGaMD2 allowed us to study the consequences of several other mutants including those affecting Arg13 and Arg129. We were able to identify several conformational types by cluster analysis. Analysis of the simulation trajectories revealed the causes of the impaired pentasaccharide binding including pentasaccharide subunit conformational changes and altered allosteric pathways in the AT protein. Our results provide insights into the effects of AT mutations interfering with heparin binding at an atomic level and can facilitate the design or interpretation of in vitro experiments.
Topics: Heparin; Molecular Dynamics Simulation; Binding Sites; Humans; Antithrombins; Mutation; Protein Binding; Oligosaccharides
PubMed: 38927061
DOI: 10.3390/biom14060657 -
Biologicals : Journal of the... Jun 2024Convalescent plasma was proposed for passive immunization against COVID-19; but so far there are conflicting results and still open questions. However, besides...
Convalescent plasma was proposed for passive immunization against COVID-19; but so far there are conflicting results and still open questions. However, besides antibodies, other plasma proteins may be good candidates for further research and application. Thromboinflammation frequently complicates severe COVID-19, and classical anticoagulants like heparins seem to have limited effect. The natural protease inhibitors antithrombin III (ATIII), α-antitrypsin (α-AT) and α-macroglobulin (α-M), which are found decreased in severe COVD-19, play a crucial role in prothrombotic and inflammatory pathways. While ATIII and α-AT are licensed as commercially prepared therapeutic concentrates, there is no preparation of α-M available. The diagnostic, prognostic, and even therapeutic potential of plasma protease inhibitors should be further explored.
PubMed: 38924809
DOI: 10.1016/j.biologicals.2024.101781 -
Clinical Cardiology Jun 2024This study evaluates the cost-effectiveness of Apixaban and Rivaroxaban, compared to Warfarin, for stroke prevention in patients with non-valvular atrial fibrillation in... (Comparative Study)
Comparative Study
Cost-Effectiveness and Budget Impact Analysis of Apixaban and Rivaroxaban Versus Warfarin in the Prevention of Stroke in Patients With Non-Valvular Atrial Fibrillation (NVAF) in Iran.
INTRODUCTION
This study evaluates the cost-effectiveness of Apixaban and Rivaroxaban, compared to Warfarin, for stroke prevention in patients with non-valvular atrial fibrillation in Iran.
METHOD
A Markov model with a 30-year time horizon was employed to simulate and assess different treatment strategies' cost-effectiveness. The study population comprised Iranian adults with NVAF, identified through specialist consultations, hospital visits, and archival record reviews. Direct medical costs, direct nonmedical, and indirect costs were included. Quality-adjusted life years (QALY) were assessed using an EQ-5D questionnaire. This study utilized a cost-effectiveness threshold of $11 134 per QALY.
RESULTS
Apixaban demonstrated superior cost-effectiveness compared to Rivaroxaban and Warfarin. Over 30 years, total costs were lower in the Apixaban and Rivaroxaban groups compared to the Warfarin group ($126.18 and $109.99 vs. $150.49). However, Apixaban showed higher total QALYs gained compared to others (0.134 vs. 0.133 and 0.116). The incremental cost-effectiveness ratio for comparing Apixaban to Warfarin was calculated at -1332.83 cost per QALY, below the threshold of $11 134, indicating Apixaban's cost-effectiveness. Sensitivity analyses confirmed the robustness of the findings, with ICER consistently remaining below the threshold. Over 5 years (2024-2028) of Apixaban usage, the incremental cost starts at USD 70 250 296 in the first year and gradually rises to USD 71 770 662 in the fifth year. DSA and PSA were assessed to prove the robustness of the results.
CONCLUSION
This study shows that Apixaban is a cost-effective option for stroke prevention in non-valvular atrial fibrillation patients in Iran compared to Warfarin.
Topics: Humans; Atrial Fibrillation; Pyrazoles; Cost-Benefit Analysis; Pyridones; Warfarin; Iran; Stroke; Rivaroxaban; Anticoagulants; Male; Factor Xa Inhibitors; Quality-Adjusted Life Years; Female; Markov Chains; Aged; Drug Costs; Treatment Outcome; Middle Aged; Budgets; Time Factors
PubMed: 38923583
DOI: 10.1002/clc.24311 -
Clinical Interventions in Aging 2024Rivaroxaban, a non-vitamin K antagonist oral anticoagulant, has become widely used for the management of venous thromboembolism (VTE) in adult patients. However, few...
BACKGROUND
Rivaroxaban, a non-vitamin K antagonist oral anticoagulant, has become widely used for the management of venous thromboembolism (VTE) in adult patients. However, few trials have explored the efficacy and safety of rivaroxaban in VTE patients over 80 years of age. This necessitates further real-world studies of rivaroxaban across elderly populations.
METHODS
We performed a retrospective single center study involving extremely aged VTE sufferers treated with rivaroxaban. The sample comprised 121 patients newly initiated on rivaroxaban diagnosed between January 2018 and January 2020. Patients were followed up for no less than 2 years. The effectiveness outcome was the disappearance of thromboembolism. The safety outcome was the incidence of major bleeding events. Comorbidities and complications were recorded throughout the entire study.
RESULTS
The efficacy outcome occurred in 114 of 121 patients (94.21%) and the safety outcome occurred in 12 of 121 patients (9.91%). Increased hemorrhages were observed in patients with infection (15.15% vs 7.80%), but no significant difference was observed due to limited sample size (P=0.3053). Patients with an age-adjusted Charlson comorbidity index score higher than 6 points exhibited higher bleeding rates (14.08% vs 4.00%; P=0.0676) and lower thrombus cure rates (88.73% vs 100%; P=0.0203).
KEY CONCLUSIONS
Patients with infection should be more careful of bleeding events during rivaroxaban therapy. An age-adjusted Charlson comorbidity index score higher than 6, which predicted poor survival, indicated inferior safety and efficacy of rivaroxaban.
AIM
To investigate the efficacy and safety of Rivaroxaban in an aged venous thromboembolism patient population under real-world conditions.
Topics: Humans; Rivaroxaban; Retrospective Studies; Male; Female; Venous Thromboembolism; Aged, 80 and over; Factor Xa Inhibitors; Hemorrhage; Cross-Sectional Studies; Treatment Outcome; Comorbidity
PubMed: 38915432
DOI: 10.2147/CIA.S405075 -
Journal of Intensive Care Jun 2024There is no reliable indicator that can assess the treatment effect of anticoagulant therapy for sepsis-associated disseminated intravascular coagulation (DIC) in the...
BACKGROUND
There is no reliable indicator that can assess the treatment effect of anticoagulant therapy for sepsis-associated disseminated intravascular coagulation (DIC) in the short term. The aim of this study is to develop and validate a prognostic index identifying 28-day mortality in septic DIC patients treated with antithrombin concentrate after a 3-day treatment.
METHODS
The cohort for derivation was established utilizing the dataset from post-marketing surveys, while the cohort for validation was acquired from Japan's nationwide sepsis registry data. Through univariate and multivariate analyses, variables that were independently associated with 28-day mortality were identified within the derivation cohort. Risk variables were then assigned a weighted score based on the risk prediction function, leading to the development of a composite index. Subsequently, the area under the receiver operating characteristic curve (AUROC). 28-day survival was compared by Kaplan-Meier analysis.
RESULTS
In the derivation cohort, 252 (16.9%) of the 1492 patients deceased within 28 days. Multivariable analysis identified DIC resolution (hazard ratio [HR]: 0.31, 95% confidence interval [CI]: 0.22-0.45, P < 0.0001) and rate of Sequential Organ Failure Assessment (SOFA) score change (HR: 0.42, 95% CI: 0.36-0.50, P < 0.0001) were identified as independent predictors of death. The composite prognostic index (CPI) was constructed as DIC resolution (yes: 1, no: 0) + rate of SOFA score change (Day 0 SOFA score-Day 3 SOFA score/Day 0 SOFA score). When the CPI is higher than 0.19, the patients are judged to survive. Concerning the derivation cohort, AUROC for survival was 0.76. As for the validation cohort, AUROC was 0.71.
CONCLUSION
CPI can predict the 28-day survival of septic patients with DIC who have undergone antithrombin treatment. It is simple and easy to calculate and will be useful in practice.
PubMed: 38915122
DOI: 10.1186/s40560-024-00739-x -
Scientific Reports Jun 2024Coagulopathy, microvascular alterations and concomitant organ dysfunctions are hallmarks of sepsis. Attempts to attenuate coagulation activation with an inhibitor of...
Coagulopathy, microvascular alterations and concomitant organ dysfunctions are hallmarks of sepsis. Attempts to attenuate coagulation activation with an inhibitor of tissue factor (TF), i.e. tissue factor pathway inhibitor (TFPI), revealed no survival benefit in a heterogenous group of sepsis patients, but a potential survival benefit in patients with an international normalized ratio (INR) < 1.2. Since an increased TF/TFPI ratio determines the procoagulant activity specifically on microvascular endothelial cells in vitro, we investigated whether TF/TFPI ratio in blood is associated with INR alterations, organ dysfunctions, disseminated intravascular coagulation (DIC) and outcome in septic shock. Twenty-nine healthy controls (HC) and 89 patients with septic shock admitted to a tertiary ICU were analyzed. TF and TFPI in blood was analyzed and related to organ dysfunctions, DIC and mortality. Patients with septic shock had 1.6-fold higher levels of TF and 2.9-fold higher levels of TFPI than HC. TF/TFPI ratio was lower in septic shock compared to HC (0.003 (0.002-0.005) vs. 0.006 (0.005-0.008), p < 0.001). Non-survivors had higher TFPI levels compared to survivors (43038 (29354-54023) vs. 28041 (21675-46582) pg/ml, p = 0.011). High TFPI levels were associated with acute kidney injury, liver dysfunction, DIC and disease severity. There was a positive association between TF/TFPI ratio and troponin T (b = 0.531 (0.309-0.754), p < 0.001). A high TF/TFPI ratio is exclusively associated with myocardial injury but not with other organ dysfunctions. Systemic TFPI levels seem to reflect disease severity. These findings point towards a pathophysiologic role of TF/TFPI in sepsis-induced myocardial injury.
Topics: Humans; Shock, Septic; Thromboplastin; Male; Female; Lipoproteins; Middle Aged; Aged; Multiple Organ Failure; Disseminated Intravascular Coagulation; Case-Control Studies; Adult; Biomarkers
PubMed: 38914630
DOI: 10.1038/s41598-024-65262-3 -
Scientific Reports Jun 2024The number of patients with atrial fibrillation is increasing, and frailty prevalence increases with age, posing challenges for physicians in prescribing anticoagulants... (Observational Study)
Observational Study
The number of patients with atrial fibrillation is increasing, and frailty prevalence increases with age, posing challenges for physicians in prescribing anticoagulants to such patients because of possible harm. The effects of frailty on anticoagulant therapy in older Japanese patients with nonvalvular atrial fibrillation (NVAF) are unclear. Herein, we prescribed rivaroxaban to Japanese patients with NVAF and monitored for a mean of 2.0 years. The primary endpoint was stroke or systemic embolism. The secondary endpoints were all-cause or cardiovascular death, composite endpoint, and major or non-major bleeding. Frailty was assessed using the Japanese long-term care insurance system. A multiple imputation technique was used for missing data. The propensity score (PS) was obtained to estimate the treatment effect of frailty and was used to create two PS-matched groups. Overall, 5717 older patients had NVAF (mean age: 73.9 years), 485 (8.5%) were classified as frail. After PS matching, background characteristics were well-balanced between the groups. Rivaroxaban dosages were 10 and 15 mg/day for approximately 80% and the remaining patients, respectively. Frailty was not associated with the primary endpoint or secondary endpoints. In conclusion, frailty does not affect the effectiveness or safety of rivaroxaban anticoagulant therapy in older Japanese patients with NVAF.Trial registration: UMIN000019135, NCT02633982.
Topics: Humans; Atrial Fibrillation; Aged; Male; Female; Frailty; Rivaroxaban; Aged, 80 and over; Anticoagulants; Japan; Stroke; Frail Elderly; Hemorrhage; Factor Xa Inhibitors; East Asian People
PubMed: 38909144
DOI: 10.1038/s41598-024-65237-4 -
The Journal of International Medical... Jun 2024The gold standard therapy for end-stage heart failure is cardiac transplantation. However, in the face of a donor shortage, a mechanical assist device such as the left...
The gold standard therapy for end-stage heart failure is cardiac transplantation. However, in the face of a donor shortage, a mechanical assist device such as the left ventricular assist device HeartMate 3 (Abbott Laboratories, Abbott Park, IL, USA) serves as bridging therapy to transplantation and/or destination therapy. Current guidelines recommend anticoagulation with a vitamin K antagonist in combination with low-dose aspirin. We herein report a challenging anticoagulation regimen in a patient with a HeartMate 3 in whom systemic anticoagulation with warfarin was not feasible for 4 years because of low compatibility and a rare X-factor deficiency. This is a rare hematological disorder, estimated to affect approximately 1 in every 500,000 to 1,000,000 people in the general population. The patient finally received a modified anticoagulation regimen involving the combination of rivaroxaban and clopidogrel without warfarin. Under this regimen, the patient remained free of thromboembolic complications for 4 years with placement of the left ventricular assist device. This case illustrates that under specific circumstances, long-term absence of warfarin therapy is feasible in patients with a HeartMate 3.
Topics: Humans; Heart-Assist Devices; Warfarin; Thromboembolism; Anticoagulants; Male; Heart Failure; Middle Aged; Clopidogrel; Rivaroxaban; Withholding Treatment
PubMed: 38901839
DOI: 10.1177/03000605241258474