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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 -
Journal of Thrombosis and Haemostasis :... Jun 2015The utility of using genetic information to guide warfarin dosing has remained unclear based on prior observational studies and small clinical trials. Two larger trials... (Review)
Review
The utility of using genetic information to guide warfarin dosing has remained unclear based on prior observational studies and small clinical trials. Two larger trials of warfarin and one of the acenocoumarol and phenprocoumon have recently been published. The COAG trial addressed the incremental benefit of adding genetic information to clinical information and demonstrated no benefit from the pharmacogenetic-based dosing strategy on the primary outcome. The EU-PACT UK trial compared an algorithm approach using genetic and clinical information to one that used a relatively fixed starting dose. The pharmacogenetic-based algorithms improved the primary outcome. The study of acenocoumarol and phenprocoumon compared a pharmacogenetic with a clinical algorithm and demonstrated no benefit on the primary outcome. The evidence to date does not support an incremental benefit of adding genetic information to clinical information on anticoagulation control. However, compared with fixed dosing, a pharmacogenetic algorithm can improve anticoagulation control.
Topics: Algorithms; Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Drug Dosage Calculations; Drug Monitoring; Genotype; Humans; Pharmacogenetics; Phenotype; Precision Medicine; Predictive Value of Tests; Treatment Outcome; Warfarin
PubMed: 26149035
DOI: 10.1111/jth.12978 -
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 -
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 -
Journal of the American College of... Sep 2014Chronic oral anticoagulant therapy is recommended (class I) in patients with mechanical heart valves and in patients with atrial fibrillation with a CHA2DS2-VASc... (Review)
Review
Chronic oral anticoagulant therapy is recommended (class I) in patients with mechanical heart valves and in patients with atrial fibrillation with a CHA2DS2-VASc (Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, prior Stroke or transient ischemic attack or thromboembolism, Vascular disease, Age 65 to 74 years, Sex category) score ≥1. When these patients undergo percutaneous coronary intervention with stenting, treatment with aspirin and a P2Y12 receptor inhibitor also becomes indicated. Before 2014, guidelines recommended the use of triple therapy (vitamin K antagonists, aspirin, and clopidogrel) for these patients. However, major bleeding is increasingly recognized as the Achilles' heel of the triple therapy regimen. Lately, various studies have investigated this topic, including a prospective randomized trial, and the evidence for adding aspirin to the regimen of vitamin K antagonists and clopidogrel seems to be weakened. In this group of patients, the challenge is finding the optimal equilibrium to prevent thromboembolic events, such as stent thrombosis and thromboembolic stroke, without increasing bleeding risk.
Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Clopidogrel; Humans; Percutaneous Coronary Intervention; Randomized Controlled Trials as Topic; Ticlopidine; Vitamin K
PubMed: 25236521
DOI: 10.1016/j.jacc.2014.06.1193 -
British Journal of Clinical Pharmacology May 2019
Topics: Acenocoumarol; Adult; Aged; Aged, 80 and over; Anticoagulants; Antitussive Agents; Cough; Drug Interactions; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Netherlands; Nonprescription Drugs; Noscapine; Phenprocoumon; Thromboembolism
PubMed: 30809820
DOI: 10.1111/bcp.13887 -
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 -
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