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Circulation Jan 2023Non-vitamin K oral anticoagulants have become the standard therapy for preventing stroke and ischemic thromboembolism in most patients with atrial fibrillation (AF). The... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Non-vitamin K oral anticoagulants have become the standard therapy for preventing stroke and ischemic thromboembolism in most patients with atrial fibrillation (AF). The effectiveness and safety of non-vitamin K oral anticoagulants in patients on hemodialysis is not well known.
METHODS
From June 2017 through May 2022, AXADIA-AFNET 8 (Compare Apixaban and Vitamin K Antagonists in Patients With Atrial Fibrillation and End-Stage Kidney Disease), an investigator-initiated PROBE (prospective randomized open blinded end point) outcome assessment trial, randomized patients with AF on chronic hemodialysis to either apixaban (2.5 mg BID) or the vitamin K antagonist (VKA) phenprocoumon (international normalized ratio, 2.0 to 3.0). The composite primary safety outcome was defined by a first event of major bleeding, clinically relevant nonmajor bleeding, or all-cause death. The primary efficacy outcome was a composite of ischemic stroke, all-cause death, myocardial infarction, and deep vein thrombosis or pulmonary embolism. Our hypothesis was that apixaban is noninferior to VKA.
RESULTS
Thirty-nine sites randomized 97 patients (30% women; mean age 75 years; mean CHADS-VASc [congestive heart failure, hypertension, age ≥75 years, diabetes, stroke or transient ischemic attack, vascular disease, age 65 to 74 years, female sex] score, 4.5; baseline characteristics balanced between groups): 48 to apixaban and 49 to VKA. The median follow-up time was 429 days (range, 37 to 1370) versus 506 days (range, 101 to 1379), respectively. Adherence to apixaban was >80% in 44 of 48 patients; the median time in therapeutic range on VKA was 50.7%. Composite primary safety outcome events occurred in 22 patients (45.8%) on apixaban and in 25 patients (51.0%) on VKA (hazard ratio, 0.93 [95% CI, 0.53-1.65]; =0.157). Composite primary efficacy outcome events occurred in 10 patients (20.8%) on apixaban and in 15 patients (30.6%) on VKA (=0.51; log rank). There were no significant differences regarding individual outcomes (all-cause mortality, 18.8% versus 24.5%; major bleeding, 10.4% versus 12.2%; and myocardial infarction, 4.2% versus 6.1%, respectively).
CONCLUSIONS
In this randomized trial comparing apixaban and VKA in patients with AF on hemodialysis with long follow-up, no differences were observed in safety or efficacy outcomes. Even on oral anticoagulation, patients with AF on hemodialysis remain at high risk of cardiovascular events. Larger randomized trials are needed to determine the optimal anticoagulation regimen for patients with AF on hemodialysis.
REGISTRATION
URL: https://www.
CLINICALTRIALS
gov; Unique identifier: NCT02933697.
Topics: Humans; Female; Aged; Male; Phenprocoumon; Atrial Fibrillation; Prospective Studies; Anticoagulants; Stroke; Hemorrhage; Pyridones; Renal Dialysis; Myocardial Infarction; Treatment Outcome
PubMed: 36335915
DOI: 10.1161/CIRCULATIONAHA.122.062779 -
The Lancet. Neurology May 2021Cervical artery dissection is a major cause of stroke in young people (aged <50 years). Historically, clinicians have preferred using oral anticoagulation with vitamin K... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Cervical artery dissection is a major cause of stroke in young people (aged <50 years). Historically, clinicians have preferred using oral anticoagulation with vitamin K antagonists for patients with cervical artery dissection, although some current guidelines-based on available evidence from mostly observational studies-suggest using aspirin. If proven to be non-inferior to vitamin K antagonists, aspirin might be preferable, due to its ease of use and lower cost. We aimed to test the non-inferiority of aspirin to vitamin K antagonists in patients with cervical artery dissection.
METHODS
We did a multicentre, randomised, open-label, non-inferiority trial in ten stroke centres across Switzerland, Germany, and Denmark. We randomly assigned (1:1) patients aged older than 18 years who had symptomatic, MRI-verified, cervical artery dissection within 2 weeks before enrolment, to receive either aspirin 300 mg once daily or a vitamin K antagonist (phenprocoumon, acenocoumarol, or warfarin; target international normalised ratio [INR] 2·0-3·0) for 90 days. Randomisation was computer-generated using an interactive web response system, with stratification according to participating site. Independent imaging core laboratory adjudicators were masked to treatment allocation, but investigators, patients, and clinical event adjudicators were aware of treatment allocation. The primary endpoint was a composite of clinical outcomes (stroke, major haemorrhage, or death) and MRI outcomes (new ischaemic or haemorrhagic brain lesions) in the per-protocol population, assessed at 14 days (clinical and MRI outcomes) and 90 days (clinical outcomes only) after commencing treatment. Non-inferiority of aspirin would be shown if the upper limit of the two-sided 95% CI of the absolute risk difference between groups was less than 12% (non-inferiority margin). This trial is registered with ClinicalTrials.gov, NCT02046460.
FINDINGS
Between Sept 11, 2013, and Dec 21, 2018, we enrolled 194 patients; 100 (52%) were assigned to the aspirin group and 94 (48%) were assigned to the vitamin K antagonist group. The per-protocol population included 173 patients; 91 (53%) in the aspirin group and 82 (47%) in the vitamin K antagonist group. The primary endpoint occurred in 21 (23%) of 91 patients in the aspirin group and in 12 (15%) of 82 patients in the vitamin K antagonist group (absolute difference 8% [95% CI -4 to 21], non-inferiority p=0·55). Thus, non-inferiority of aspirin was not shown. Seven patients (8%) in the aspirin group and none in the vitamin K antagonist group had ischaemic strokes. One patient (1%) in the vitamin K antagonist group and none in the aspirin group had major extracranial haemorrhage. There were no deaths. Subclinical MRI outcomes were recorded in 14 patients (15%) in the aspirin group and in 11 patients (13%) in the vitamin K antagonist group. There were 19 adverse events in the aspirin group, and 26 in the vitamin K antagonist group.
INTERPRETATION
Our findings did not show that aspirin was non-inferior to vitamin K antagonists in the treatment of cervical artery dissection.
FUNDING
Swiss National Science Foundation, Swiss Heart Foundation, Stroke Funds Basel, University Hospital Basel, University of Basel, Academic Society Basel.
Topics: Acenocoumarol; Adult; Anticoagulants; Aspirin; Carotid Artery, Internal, Dissection; Denmark; Female; Germany; Humans; Male; Middle Aged; Phenprocoumon; Platelet Aggregation Inhibitors; Stroke; Switzerland; Vertebral Artery Dissection; Warfarin
PubMed: 33765420
DOI: 10.1016/S1474-4422(21)00044-2 -
Thrombosis Journal Mar 2021Determination of anticoagulant therapy is of pronounced interest in emergency situations. However, routine tests do not provide sufficient insight. This study was...
BACKGROUND
Determination of anticoagulant therapy is of pronounced interest in emergency situations. However, routine tests do not provide sufficient insight. This study was performed to investigate the impact of anticoagulants on the results of viscoelastometric assays using the ClotPro device.
METHODS
This prospective, observational study was conducted in patients receiving dabigatran, factor Xa (FXa)-inhibitors, phenprocoumon, low molecular weight heparin (LMWH) or unfractionated heparin (UFH) (local ethics committee approval number: 17-525-4). Healthy volunteers served as controls. Viscoelastometric assays were performed, including the extrinsic test (EX-test), intrinsic test (IN-test) Russel's viper venom test (RVV-test), ecarin test (ECA-test), and the tissue plasminogen activator test (TPA-test).
RESULTS
70 patients and 10 healthy volunteers were recruited. Clotting time in the EX-test (CT) was significantly prolonged versus controls by dabigatran, FXa inhibitors and phenprocoumon. CT was prolonged by dabigatran, FXa inhibitors and UFH. Dabigatran, FXa inhibitors and UFH significantly prolonged CT in comparison with controls (median 200, 207 and 289 vs 63 s, respectively; all p < 0.0005). Only dabigatran elicited a significant increase in CT compared to controls (median 307 vs 73 s; p < 0.0001). CT correlated strongly with dabigatran plasma concentration (measured by anti-IIa activity; r = 0.9970; p < 0.0001) and provided 100% sensitivity and 100% specificity for detecting dabigatran. Plasma concentrations (anti-XA activity) of FXa inhibitors correlated with CT (r = 0.7998; p < 0.0001), and CT provided 83% sensitivity and 64% specificity for detecting FXa inhibitors.
CONCLUSIONS
In emergency situations, ClotPro viscoelastometric assessment of whole-blood samples may help towards determining the presence and type of anticoagulant class that a patient is taking.
TRIAL REGISTRATION
German clinical trials database ID: DRKS00015302 .
PubMed: 33726769
DOI: 10.1186/s12959-021-00267-w -
Thrombosis Journal May 2022For stroke prevention in patients with atrial fibrillation (AF), direct oral anticoagulants (DOACs) have been increasingly prescribed instead of vitamin-K-antagonists...
BACKGROUND
For stroke prevention in patients with atrial fibrillation (AF), direct oral anticoagulants (DOACs) have been increasingly prescribed instead of vitamin-K-antagonists (VKA). For some patients a lower dosage of DOACs (ld-DOACs) is recommended. Ld-DOAC prescribing seems to be common, although previous studies did not show clear superiority of ld-DOACs over warfarin. In Germany, phenprocoumon is used almost exclusively as VKA. Randomized controlled trials comparing DOACs and phenprocoumon in the general population of patients with AF do not exist. Therefore, we aimed to compare ld-DOACs and phenprocoumon in a real-world setting in Germany.
METHODS
In a retrospective observational cohort study, claims data from a group of small to medium-sized health insurance companies were analysed. Risks for the outcomes thromboembolism, death and major bleeding were estimated by Cox regression. Out of 93,685 patients with atrial fibrillation and a first prescription of an oral anticoagulant, 20,179 receiving VKA and 21,724 ld-DOACs (29.6% of all DOAC patients) were included. For the sensitivity analysis phenprocoumon was compared to the five ld-DOAC groups (ld-apixaban, ld-dabigatran, ld-edoxaban, ld-rivaroxaban, and the composite of all ld-DOACs) after propensity-score matching.
RESULTS
Phenprocoumon was associated with statistically significant fewer thromboembolic events (HR = 1.29, 95% CI [1.13, 1.48], p < .001) and deaths (HR = 1.52, 95% CI [1.41, 1.63], p < .001) and a non-significant higher bleeding risk (HR = 0.89, 95% CI [0.79, 1.00], p = .051) than composite ld-DOAC. Regarding the subgroups, only patients with ld-apixaban had a statistically significant higher risk for thromboembolic events (HR = 1.42, 95% CI [1.21, 1.65], p < .001) and a lower bleeding risk (HR = 0.75, 95% CI [0.65, 0.86], p < .001). Ld-apixaban, ld-edoxaban, and ld-rivaroxaban were associated with a higher risk of death. The sensitivity analysis confirmed these associations.
CONCLUSION
Phenprocoumon seems to be superior to ld-DOACs for patients with AF. As a hypothesis phenprocoumon might turn out to be the wiser choice for high-risk patients with AF as compared to ld-DOACs, especially regarding thromboembolic events and death. Therefore, RCTs comparing ld-DOACs with phenprocoumon are needed.
PubMed: 35619140
DOI: 10.1186/s12959-022-00389-9 -
BMJ Open Jan 2023Direct oral anticoagulants (DOACs) were introduced based on randomised controlled trials (RCTs) comparing them to vitamin-K-antagonist (VKA) warfarin. In Germany, almost... (Observational Study)
Observational Study
OBJECTIVES
Direct oral anticoagulants (DOACs) were introduced based on randomised controlled trials (RCTs) comparing them to vitamin-K-antagonist (VKA) warfarin. In Germany, almost exclusively phenprocoumon is used as VKA. RCTs with phenprocoumon being absent we analysed the benefits and harms of DOACs and phenprocoumon for patients with atrial fibrillation (AF) in a real-world setting.
DESIGN
In a retrospective observational cohort study, claims data covering inpatient and outpatient care from 2015 to 2019 were analysed by Cox regression and propensity score matching (PSM).
SETTING
Data from a group of small-sized to medium-sized health insurance companies in Germany.
PARTICIPANTS
We analysed datasets of 71 961 patients with AF and first prescription of phenprocoumon (n=20 179) or DOAC in standard dose (n=51 782). Patients with reduced dose of DOACs were excluded (n=21 724).
OUTCOME MEASURES
Outcomes were thromboembolic events, major bleeding and death during a 12-month follow-up period.
RESULTS
The regression analysis widely showed similarity between phenprocoumon and standard dose DOACs regarding effectiveness and safety. There were only three statistically significant differences: a lower bleeding risk with composite DOACs and apixaban (HR (95% CI) = 0.67 (0.59 to 0.76) and 0.54 (0.46 to 0.63), respectively) and a higher risk of death with rivaroxaban (1.21 (1.10 to 2.34)). The analysis after PSM was consistent with the first two results regarding composite DOACs and apixaban (number needed to treat, NNT 101 and 78) and showed a lower bleeding risk with rivaroxaban (NNT 156). Absolute differences were small.
CONCLUSIONS
The small superiority or non-inferiority of DOACs over warfarin seen in the RCTs might not translate into relevant advantages of DOACs over phenprocoumon. To confirm the hypothesis, an RCT with phenprocoumon is needed. Next to the safety and effectiveness assessments other factors might also play a substantial role in the decision on the right OAC for stroke prevention.
Topics: Humans; Phenprocoumon; Atrial Fibrillation; Warfarin; Rivaroxaban; Administration, Oral; Anticoagulants; Pyridones; Vitamins; Stroke; Retrospective Studies
PubMed: 36593002
DOI: 10.1136/bmjopen-2022-063490 -
Molecules (Basel, Switzerland) Mar 2020Many natural coumarins and their chemically synthesized analogs and derivatives exert diverse properties, such as anticancer, antioxidant, anti-inflammatory, or... (Review)
Review
Many natural coumarins and their chemically synthesized analogs and derivatives exert diverse properties, such as anticancer, antioxidant, anti-inflammatory, or anticoagulant, with the latter being of the utmost importance. The widely used warfarin, acenocoumarol, and phenprocoumon exert anticoagulant properties by inhibiting the vitamin K epoxide reductase complex. In this interdisciplinary review, we present biochemical principles of the coagulation processes and possible methods for their tuning based on the use of coumarins. We also summarize chemical methods of synthesis of coumarins and discuss structures and properties of those that have been used for a long time, as well as newly synthesized compounds. Brief information on the clinical use of coumarins and other anticoagulant drugs is given, including the severe effects of overdosing and methods for reversing their action.
Topics: Animals; Cardiovascular Diseases; Coumarins; Factor Xa Inhibitors; Humans; Vitamin K
PubMed: 32213944
DOI: 10.3390/molecules25061465 -
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 -
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 -
Frontiers in Pharmacology 2019Dose requirements of vitamin K antagonists are associated with and , but, compared to warfarin, less data is available about phenprocoumon. Furthermore, the effects on...
BACKGROUND
Dose requirements of vitamin K antagonists are associated with and , but, compared to warfarin, less data is available about phenprocoumon. Furthermore, the effects on dose stability and anticoagulation quality are still unclear.
METHODS
Aim was to scrutinize phenprocoumon dose requirements, dose stability and anticoagulation quality in association to and in a natural cohort of elderly primary care patients. As a subgroup within the IDrug study, phenprocoumon treated patients with at least two INR values within three months before enrollment (n = 209) were analyzed concerning average weekly dose, standard deviation of weekly dose (intra-subject variability), constant dose (yes/no), average INR and TTR grouped by and (and combinations).
RESULTS
Average weekly dose per patient was 14.4 ± 5.3 mg, 11.9 ± 4.0 mg and 11.2 ± 4.3 mg in wildtypes, and carriers (p < .0001) and 16.0 ± 4.2 mg, 13.3 ± 5.1 mg and 8.0 ± 2.7 mg per week in CC, CT and TT genotypes, respectively (p < .0001). Significant differences concerning intra-subject variability were detected among all groups (p < .0001) with the smallest variability in carriers. TTR medians were 75.4%, 79.4% and 100% in wildtypes, and carriers, respectively (p = 0.0464). The proportion of patients with perfect control was highest among carriers, but this result was not significant (p = 0.0713).
DISCUSSION
Our analyses support the results of previous investigations regarding genotype-associated dose requirements and raise the hypothesis that dose stability and anticoagulation quality may be increased in carriers. However, our data should be treated cautiously due to the small sample size.
CLINICAL TRIAL REGISTRATION
German Clinical Trials Register, identifier DRKS00006256.
PubMed: 32047440
DOI: 10.3389/fphar.2019.01620