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Der Nervenarzt Feb 2024To investigate the prevalence of coincident anticoagulation in patients with cognitive disorders and possible or probable cerebral amyloid angiopathy (CAA) as well as...
OBJECTIVES
To investigate the prevalence of coincident anticoagulation in patients with cognitive disorders and possible or probable cerebral amyloid angiopathy (CAA) as well as the relationship between the presence of oral anticoagulation and CAA-specific lesion load.
MATERIALS AND METHODS
Patients with subjective cognitive decline (SCD), amnestic and non-amnestic mild cognitive impairment (aMCI/naMCI), Alzheimer's disease (AD), mixed dementia (MD) and vascular dementia (VD) who presented to our outpatient dementia clinic between February 2016 and October 2020 were included in this retrospective analysis. Patients underwent cranial magnetic resonance imaging (MRI). MRI data sets were analyzed regarding the presence of CAA-related MRI biomarkers to determine CAA prevalence. Presence of anticoagulant therapy was determined by chart review.
RESULTS
Within the study period, 458 patients (209 male, 249 female, mean age 73.2 ± 9.9 years) with SCD (n = 44), naMCI (n = 40), aMCI (n = 182), AD (n = 120), MD (n = 68) and VD (n = 4) were analyzed. A total of 109 patients (23.8%) were diagnosed with possible or probable CAA. CAA prevalence was highest in aMCI (39.4%) and MD (28.4%). Of patients with possible or probable CAA, 30.3% were under platelet aggregation inhibition, 12.8% were treated with novel oral anticoagulants and 3.7% received phenprocoumon treatment. Regarding the whole study cohort, patients under oral anticoagulation showed more cerebral microbleeds (p = 0.047). There was no relationship between oral anticoagulation therapy and the frequency of cortical superficial siderosis (p = 0.634).
CONCLUSION
CAA is a frequent phenomenon in older patients with cognitive disorders. Almost half of CAA patients receive anticoagulant therapy. Oral anticoagulation is associated with a higher number of cortical and subcortical microbleeds.
Topics: Humans; Male; Female; Aged; Middle Aged; Aged, 80 and over; Retrospective Studies; Cerebral Hemorrhage; Prevalence; Cerebral Amyloid Angiopathy; Magnetic Resonance Imaging; Cognitive Dysfunction; Alzheimer Disease; Anticoagulants
PubMed: 37747503
DOI: 10.1007/s00115-023-01547-8 -
Innere Medizin (Heidelberg, Germany) Apr 2024A 73-year-old man with dementia was referred to our clinic with hypernatremia and volume depletion. New-onset neurogenic dysphagia was likely the reason for both. The...
A 73-year-old man with dementia was referred to our clinic with hypernatremia and volume depletion. New-onset neurogenic dysphagia was likely the reason for both. The patient had chronic embolic strokes on the computed tomography (CT) images. Documentation from previous hospitalizations in different hospitals revealed a repeatedly prolonged activated partial thromboplastin time (aPTT); 5 years prior, antiphospholipid antibody syndrome had already been suspected, but the necessary workup was never completed. We diagnosed the patient with primary antiphospholipid antibody syndrome and initiated therapy with vitamin K antagonists (phenprocoumon) and aspirin.
Topics: Male; Humans; Aged; Antiphospholipid Syndrome; Anticoagulants; Phenprocoumon; Fibrinolytic Agents
PubMed: 37728737
DOI: 10.1007/s00108-023-01581-3 -
Clinical Epidemiology 2023Over the last decade, the use of direct oral anticoagulants (DOACs) has strongly increased. We aimed to describe and compare risk profiles including potential changes...
PURPOSE
Over the last decade, the use of direct oral anticoagulants (DOACs) has strongly increased. We aimed to describe and compare risk profiles including potential changes over time among persons with non-valvular atrial fibrillation initiating treatment with different DOACs or phenprocoumon (vitamin K antagonist) between 2011 and 2019 in Germany.
PATIENTS AND METHODS
Using the German Pharmacoepidemiological Research Database (GePaRD; claims data of ~20% of the German population), we identified persons with a first dispensing of phenprocoumon or a DOAC and a diagnosis of non-valvular atrial fibrillation between August 2011 and December 2019. We described the morbidity of included patients prior to treatment initiation, stratified by year of treatment initiation.
RESULTS
Overall, we included 448,028 new users (phenprocoumon: N = 118,117, rivaroxaban: N = 130,997, apixaban: N = 130,300, edoxaban: N = 38,128, dabigatran: N = 30,486). Comparing new DOAC users in 2019, the proportion with prior ischemic stroke was highest for dabigatran (17%) and lowest for rivaroxaban (8%). The proportion with prior major bleeding was also highest for dabigatran (25%) and lowest for edoxaban (20%). New users of apixaban were oldest and, eg, showed the highest prevalence of congestive heart failure. Changes over time were most pronounced for phenprocoumon. For example, among persons initiating phenprocoumon in 2012 vs 2019, the proportion with prior major bleeding increased from 18% to 35%; the proportion with renal disease increased from 20% to 36% and the proportion with liver disease from 18% to 24%.
CONCLUSION
This study demonstrated differences in risk profiles between new users of different oral anticoagulants and substantial changes over time among new phenprocoumon users. These differences have to be considered in head-to-head comparisons of these drugs based on observational data, especially regarding potential unmeasured confounding.
PubMed: 37483262
DOI: 10.2147/CLEP.S405585 -
European Heart Journal Open Jul 2023In patients undergoing catheter ablation for atrial fibrillation (AF), direct oral anticoagulants (DOACs) are as effective and safe as the vitamin K antagonist (VKA)...
AIMS
In patients undergoing catheter ablation for atrial fibrillation (AF), direct oral anticoagulants (DOACs) are as effective and safe as the vitamin K antagonist (VKA) warfarin. Phenprocoumon has a different pharmacokinetic profile compared with warfarin and is the most used VKA in Germany. The aim of the study was to compare DOAC with phenprocoumon.
METHODS AND RESULTS
In this retrospective single-centre cohort study, 1735 patients who underwent 2219 consecutive catheter ablations for AF between January 2011 and May 2017 were included. All patients were in-hospital for at least 48 h after catheter ablation. The primary outcome was defined as peri-procedural thrombo-embolic events. The secondary outcome was any bleeding according to the International Society on Thrombosis and Haemostasis (ISTH). The mean age of the patients was 63.3 years. Phenprocoumon was prescribed in 929 (42%) of the cases, and in 697 (31%) dabigatran, 399 (18%) rivaroxaban, and 194 (9%) apixaban. During hospitalization, 37 (1.6%) thrombo-embolic events occurred, including 23 transient ischaemic attacks (TIAs). Compared with the use of phenoprocoumon, the use of DOAC was significantly associated with a lower thrombo-embolic risk [16 (1.2%) vs. 21 (2.2%), odds ratio (OR)], 0.5 [95% confidence interval (CI) 0.2-0.9], = 0.04. No statistically significant association with bleeding risk was observed [phenprocomoun: 122 (13%); DOAC: 163 (12.6%); OR 0.9 (95% CI 0.7-1.2); = 0.70]. Interruption of oral anticoagulation (OAC) was associated with an increased risk for thrombo-embolic complications [OR 2.2 (1.1-4.3); = 0.031], and bleeding [OR 2.5 (95% CI 1.8-3.2), = 0.001].
CONCLUSION
In patients undergoing catheter ablation for AF, the use of DOAC was associated with a reduced risk of thrombo-embolic events compared with phenprocoumon. Non-interrupted oral anticoagulation (OAC) therapy was associated with a reduced risk of peri-procedural thrombo-embolic and any bleeding complications.
PubMed: 37427356
DOI: 10.1093/ehjopen/oead065 -
Thrombosis Research Aug 2023The European Medicine Agency has authorized COVID-19 vaccination in adolescents and young adults (AYAs) from 12 years onwards. In elderly vitamin K antagonist (VKA)...
INTRODUCTION
The European Medicine Agency has authorized COVID-19 vaccination in adolescents and young adults (AYAs) from 12 years onwards. In elderly vitamin K antagonist (VKA) users, COVID-19 vaccination has been associated with an increased risk of supra- and subtherapeutic INRs. Whether this association is also observed in AYAs using VKA is unknown. Our aim was to describe the stability of anticoagulation after COVID-19 vaccination in AYA VKA users.
MATERIALS AND METHODS
A case-crossover study was performed in a cohort of AYAs (12-30 years) using VKAs. The most recent INR results before vaccination, the reference period, were compared with the most recent INR after the first and, if applicable, second vaccination. Several sensitivity analyses were performed in which we restricted our analysis to stable patients and patients without interacting events.
RESULTS
101 AYAs were included, with a median age [IQR] of 25 [7] years, of whom 51.5 % were male and 68.3 % used acenocoumarol. We observed a decrease of 20.8 % in INRs within range after the first vaccination, due to an increase of 16.8 % in supratherapeutic INRs. These results were verified in our sensitivity analyses. No differences were observed after the second vaccination compared to before and after the first vaccination. Complications after vaccination occurred less often than before vaccination (9.0 vs 3.0 bleedings) and were non-severe.
CONCLUSIONS
the stability of anticoagulation after COVID-19 vaccination was decreased in AYA VKA users. However, the decrease might not be clinically relevant as no increase of complications nor significant dose adjustments were observed.
Topics: Humans; Male; Young Adult; Adolescent; Aged; Adult; Female; COVID-19 Vaccines; Cross-Over Studies; COVID-19; Anticoagulants; International Normalized Ratio; Vitamin K
PubMed: 37321159
DOI: 10.1016/j.thromres.2023.06.005 -
Europace : European Pacing,... May 2023Atrial fibrillation (AF) is a risk factor for brain infarction, which can lead to epilepsy. We aimed to investigate whether treatment of AF with direct oral...
AIMS
Atrial fibrillation (AF) is a risk factor for brain infarction, which can lead to epilepsy. We aimed to investigate whether treatment of AF with direct oral anticoagulants (DOACs) affects the risk of epilepsy in comparison to treatment with the vitamin K antagonist phenprocoumon (PPC).
METHODS AND RESULTS
We performed an active comparator, nested case-control study based on the German Pharmacoepidemiological Research Database that includes claims data from statutory health insurance providers of about 25 million persons since 2004. In 2011-17, 227 707 AF patients initiated treatment with a DOAC or PPC, of which 1828 cases developed epilepsy on current treatment with an oral anticoagulant. They were matched to 19 084 controls without epilepsy. Patients with DOAC treatment for AF had an overall higher risk of epilepsy with an odds ratio of 1.39, 95% CI (1.24; 1.55) compared to current PPC treatment. Cases had higher baseline CHA2DS2-VASc scores and more frequently a history of stroke than controls. After excluding patients with ischaemic stroke prior to the diagnosis of epilepsy, the risk of epilepsy was still higher on DOACs than on PPC. In contrast, within a cohort of patients with venous thromboembolism, the risk of epilepsy on treatment with DOACs was less elevated [adjusted odds ratio 1.15, 95% CI (0.98; 1.34)].
CONCLUSION
In patients with AF initiating oral anticoagulation, treatment with a DOAC was associated with an increased risk of epilepsy compared to the vitamin K antagonist PPC. Covert brain infarction may explain the observed elevated risk of epilepsy.
Topics: Humans; Atrial Fibrillation; Stroke; Brain Ischemia; Case-Control Studies; Anticoagulants; Phenprocoumon; Risk Factors; Vitamin K; Administration, Oral
PubMed: 37013704
DOI: 10.1093/europace/euad087 -
Cureus Jan 2023The dual coagulation disorder hereditary protein S deficiency and activated protein C (APC) resistance, which clinically manifests with recurrent venous thrombosis and...
The dual coagulation disorder hereditary protein S deficiency and activated protein C (APC) resistance, which clinically manifests with recurrent venous thrombosis and multifocal ischemic stroke, has only rarely been reported in the same patient. The patient is a 54-year-old male with a history of recurrent, asymptomatic ischemic stroke or transient ischemic attack (TIA) since age 14 and four episodes of deep vein thromboses (DVT), two complicated by pulmonary embolism, attributed to hereditary protein S deficiency and homozygous factor V Leiden mutation. In addition, the medical history was positive for obesity, previous chronic alcoholism, smoking, gynecomastia with left breast resection, arterial hypertension, hepatic steatosis, and cholecystolithiasis. Because of low compliance, long-term oral anticoagulation with phenprocoumon from the age of 38 was replaced by dabigatran (300 mg/d) after another stroke with bleeding at the age of 54. In summary, the simultaneous presence of two hereditary coagulation disorders can lead to multiple venous thromboses and recurrent ischemic stroke. An appealing therapeutic option in poorly compliant patients with these two hereditary clotting defects is the replacement of long-term anticoagulation with a vitamin K antagonist (VKA) by a direct oral anticoagulant.
PubMed: 36824536
DOI: 10.7759/cureus.34012 -
Medical Cannabis and Cannabinoids 2023Treatment with cannabis extracts for a variety of diseases has gained popularity. However, differences in herb-drug interaction potential of extracts from different...
INTRODUCTION
Treatment with cannabis extracts for a variety of diseases has gained popularity. However, differences in herb-drug interaction potential of extracts from different plant sources are poorly understood. In this study, we provide a characterization of cannabis extracts prepared from four cannabis chemotypes and an in vitro assessment of their Cytochrome P450 (CYP)-mediated herb-drug interaction profiles.
METHODS
Plant extracts were either commercially obtained or prepared using ethanol as solvent, followed by overnight decarboxylation in a reflux condenser system. The extracts were characterized for their cannabinoid content using NMR and HPLC-PDA-ELSD-ESIMS. CYP inhibition studies with the cannabis extracts and pure cannabinoids (tetrahydrocannabinol [THC] and cannabidiol [CBD]) were performed using pooled, mixed gender human liver microsomes. Tolbutamide and testosterone were used as specific substrates to assess the inhibitory potential of the extracts on CYP2C9 and CYP3A4, and the coumarinic oral anticoagulants warfarin, phenprocoumon, and acenocoumarol were studied as model compounds since in vivo herb-drug interactions have previously been reported for this compound class.
RESULTS
In accordance with the plant chemotypes, two extracts were rich in THC and CBD (at different proportions); one extract contained mostly CBD and the other mostly cannabigerol (CBG). Residual amounts of the corresponding acids were found in all extracts. The extracts with a single major cannabinoid (CBD or CBG) inhibited CYP2C9- and CYP3A4-mediated metabolism stronger than the extracts containing both major cannabinoids (THC and CBD). The inhibition of CYP3A4 and CYP2C9 by the extract containing mostly CBD was comparable to their inhibition by pure CBD. In contrast, the inhibitory potency of extracts containing both THC and CBD did not correspond to the combined inhibitory potency of pure THC and CBD. Although being structural analogs, the three coumarin derivatives displayed major differences in their herb-drug interaction profiles with the cannabis extracts and the pure cannabinoids.
CONCLUSION
Despite the fact that cannabinoids are the major components in ethanolic, decarboxylated cannabis extracts, it is difficult to foresee their herb-drug interaction profiles. Our in vitro data and the literature-based evidence on in vivo interactions indicate that cannabis extracts should be used cautiously when co-administered with drugs exhibiting a narrow therapeutic window, such as coumarinic anticoagulants, regardless of the cannabis chemotype used for extract preparation.
PubMed: 36814687
DOI: 10.1159/000528465 -
Journal of Clinical Medicine Feb 2023Hemodynamic alterations in Fontan patients (FP) are associated with hemostatic dysbalance and Fontan-associated liver disease. Studies of other hepatopathologies...
Hemodynamic alterations in Fontan patients (FP) are associated with hemostatic dysbalance and Fontan-associated liver disease. Studies of other hepatopathologies indicate an interplay between cholestasis, tissue factor (TF), and von Willebrand factor (VWF). Hence, we hypothesized a relationship between the accumulation of bile acids (BA) and these hemostatic factors in FP. We included 34 FP (Phenprocoumon = 15, acetylsalicylic acid (ASA) = 16). BA were assessed by mass spectrometry. TF activity and VWF antigen (VWF:Ag) were determined by chromogenic assays. VWF collagen-binding activity (VWF:CB) was assessed via ELISA. Cholestasis was observed in 6/34 FP (total BA ≥ 10 µM). BA levels and TF activity did not correlate ( = 0.724). Cholestatic FP had lower platelet counts ( = 0.013) from which 5/6 FP were not treated with ASA. VWF:Ag levels were increased in 9/34 FP and significantly lower in FP receiving ASA ( = 0.044). Acquired von Willebrand syndrome (AVWS) was observed in 10/34-FP, with a higher incidence in cholestatic FP (4/6) ( = 0.048). Cholestasis is unexpectedly infrequent in FP and seems to be less frequent under ASA therapy. Therefore, ASA may reduce the risk of advanced liver fibrosis. FP should be screened for AVWS to avoid bleeding events, especially in cholestatic states.
PubMed: 36769887
DOI: 10.3390/jcm12031240 -
BMJ Paediatrics Open Jan 2023Direct oral anticoagulants (DOACs) are direct inhibitors of coagulation factor Xa and are frequently used in adults for different indications such as deep vein... (Clinical Trial)
Clinical Trial
Pharmacokinetics of a microdosed cocktail of three direct oral anticoagulants in children with congenital heart defects: study protocol for a single-centre clinical trial (DOAC-Child).
INTRODUCTION
Direct oral anticoagulants (DOACs) are direct inhibitors of coagulation factor Xa and are frequently used in adults for different indications such as deep vein thrombosis or non-valvular atrial fibrillation. Paediatric patients might benefit as well from DOACs because the simplicity and convenience of their use is likely to decrease physical and psychological stress related to invasive procedures associated with phenprocoumon and heparin therapy. Thus, it is expected that the future use of DOACs will ultimately improve compliance and overall safety of anticoagulant therapies in paediatric populations. To assure safe and effective use the clinical pharmacology and pharmacokinetics (PK) of these drugs need to be evaluated in children.
METHODS AND ANALYSIS
This study is a single-centre, open-label, clinical trial in a paediatric population with non-cyanotic congenital heart defects. After having obtained informed consent from the parents, each participant will receive a single oral administration of a drinkable solution of a microdose cocktail of three FXa inhibitors consisting of apixaban (12.5 µg), rivaroxaban (12.5 µg), edoxaban (50 µg), plus a microdose of the two probe drugs midazolam (10 µg) and yohimbine (25 µg). Serial blood samples (n=up to 20) will be collected at specified time points before and up to 25 hours after cocktail administration. The primary PK endpoint will be the area under the plasma concentration time curve of apixaban, rivaroxaban and edoxaban. Secondary PK outcomes will be C, t, t, Cl/F and V/F. Safety and tolerability of the microdose cocktail will be evaluated as well by a collection of adverse events.
ETHICS
This study has been approved by the responsible Ethics Committee of the Medical Faculty of Heidelberg University.
DISSEMINATION
Study results will be presented at international scientific meetings and published in peer-reviewed journals.
TRIAL REGISTRATION NUMBER
EudraCT 2019-001759-38 16, DRKS00021455.
Topics: Adult; Child; Humans; Anticoagulants; Pyridines; Rivaroxaban; Thiazoles
PubMed: 36720501
DOI: 10.1136/bmjpo-2022-001662