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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 -
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 -
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 -
Clinical Oral Investigations May 2019Bleeding after tooth extraction range from minor bleeding to life-threating haemorrhagic shock and are among the leading complications in patients under oral...
Characteristics, treatment and outcome of bleeding after tooth extraction in patients on DOAC and phenprocoumon compared to non-anticoagulated patients-a retrospective study of emergency department consultations.
OBJECTIVES
Bleeding after tooth extraction range from minor bleeding to life-threating haemorrhagic shock and are among the leading complications in patients under oral anticoagulation with direct oral anticoagulants (DOACs) or phenprocoumon. Little is known about how anticoagulation in patients under DOAC or phenprocoumon alters the characteristics, treatment or outcome of bleeding events, in comparison to non-anticoagulated patients.
METHODS
Patients admitted to a tertiary ED in Bern, Switzerland, from June 1st 2012 to 31st May 2016 with bleeding related to tooth extraction under DOAC, phenprocoumon or without anticoagulation, were compared.
RESULTS
Out of 161,458 emergency consultations, 64 patients with bleeding from tooth extraction were included in our study. In anticoagulation groups, we found significantly more delayed bleeding events than in patients without anticoagulation (9 (81.3%) DOAC, 19 (86.4%) phenprocoumon, 8 (30.8%) no anticoagulation, p < 0.001). Anticoagulated patients had to stay longer in the ED than non-anticoagulated patients, with no significant difference between DOAC or phenprocoumon (hours: 4.8 (3.2-7.6 IQR) DOAC, 3.0 (2.0-5.5 IQR) phenprocoumon, p = 0.133; 2.7 (1.6-4.6) no anticoagulation; p = 0.039). More patients with anticoagulation therapy needed surgery than patients without anticoagulant therapy (11 (68.8%) DOAC, 12 (54.6%) VKA, p = 0.506; 7(26.9%) no anticoagulation; p = 0.020).
CONCLUSIONS
Delayed bleeding occur more often in anticoagulated patients with both DOAC and phenprocoumon compared to patients without anticoagulation. Bleeding events in anticoagulated patients with DOAC and phenprocoumon equally need longer ED treatment and more frequent surgical intervention.
CLINICAL RELEVANCE
Caution with delayed bleeding in anticoagulated patients with DOACs and phenprocoumon is necessary and treatment of bleeding is resource-demanding.
Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Emergency Service, Hospital; Female; Hemorrhage; Humans; Male; Middle Aged; Phenprocoumon; Retrospective Studies; Switzerland; Tooth Extraction; Treatment Outcome; Young Adult
PubMed: 30291493
DOI: 10.1007/s00784-018-2676-7 -
Journal of Thrombosis and Haemostasis :... Mar 2017Essentials The EU-PACT trial was used to investigate age on the interaction between coumarins and genotype. The results support the use of genotype-guided dosing for... (Randomized Controlled Trial)
Randomized Controlled Trial
UNLABELLED
Essentials The EU-PACT trial was used to investigate age on the interaction between coumarins and genotype. The results support the use of genotype-guided dosing for phenprocoumon in patients < 75 years. For patients ≥ 75 years the phenprocoumon algorithm should be revised and further tested. No influence of comorbidities and co-current drug use was found that could explain the differences.
SUMMARY
Background Age seemed to affect the interaction between coumarins and genotype in the acenocoumarol and phenprocoumon arm of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial. Objectives To investigate the effect of genotype-guided dosing stratified by age and the potential factors causing a difference. Patients/Methods Data from the acenocoumarol/phenprocoumon arm of the EU-PACT trial were used. The percentages of time below the therapeutic range, time above the therapeutic range and time in the therapeutic range (TTR) during the initial 12 weeks of therapy were compared between the genotype-guided group and the control group among younger (< 75 years) and older (≥ 75 years) patients by the use of independent t-tests, and adjusted for sex, height, weight and co-medications by the use of linear regression. Results Among younger phenprocoumon users, TTR during the first 12 weeks in the genotype-guided group (n = 55) was 9.5% (95% confidence interval [CI] 1.3 to 17.8) higher than in the control group (n = 63), with a remarkably lower percentage of time above this range (difference: - 9.6%, 95% CI - 19.0 to - 0.2) and a similar time below this range. Older patients dosed by the genotype-guided algorithm (n = 24) spent more time above the range (difference: 27.5%, 95% CI 12.9 to 42.0). For acenocoumarol users, there were no significant differences between the genotype-guided and control groups for most outcomes, except for a lower percentage of time below the range among older patients. Conclusions The genotype-guided algorithm for phenprocoumon in the EU-PACT trial benefitted younger patients more, but for older patients the algorithm needs to be revised and tested in further research.
Topics: Acenocoumarol; Age Factors; Aged; Aged, 80 and over; Algorithms; Anticoagulants; Comorbidity; Cytochrome P-450 CYP2C9; Europe; Female; Genotype; Humans; International Normalized Ratio; Male; Middle Aged; Pharmacogenetics; Phenprocoumon; Time Factors; Treatment Outcome; Vitamin K Epoxide Reductases
PubMed: 27992949
DOI: 10.1111/jth.13601 -
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 Thrombosis and Haemostasis :... Jan 2018Essentials The knowledge of quality and safety of acenocoumarol and phenprocoumon use in children is limited. We used data from a multicenter retrospective follow-up...
UNLABELLED
Essentials The knowledge of quality and safety of acenocoumarol and phenprocoumon use in children is limited. We used data from a multicenter retrospective follow-up study in children in the Netherlands. The quality of anticoagulation control in the first month of use was low, but improved thereafter. No thromboembolic events occurred, however bleeding events occurred in 1-3 out of 10 patients.
SUMMARY
Background The use of vitamin-K antagonists in pediatric patients is rare and information on the quality and safety of treatment with acenocoumarol and phenprocoumon is limited. Objectives To assess the quality, safety and effectiveness during the first year of acenocoumarol and phenprocoumon treatment in pediatric patients in the Netherlands. Methods The Children Anticoagulation and Pharmacogenetics Study (CAPS) was designed as a multicenter retrospective follow-up study. Patients who used acenocoumarol or phenprocoumon at an age of ≤ 18 years, were selected from four pediatric hospitals and one anticoagulation clinic in the Netherlands. The quality of treatment was assessed by calculating the percentage of time in therapeutic INR range (TTR) for the first month and for every 3 months of use during the first year of treatment. Effectiveness and safety were assessed by the number of thromboembolic and bleeding events. Results In total, 213 patients participated, of whom 187 (155 acenocoumarol; 32 phenprocoumon) were included in this analysis. The mean TTR was 47.0% and 51.4% in the first month of use for acenocoumarol and phenprocoumon, respectively. After the first 3 months the mean TTR for both VKAs was above 64%. In 14.6% (acenocoumarol) and 31.3% (phenprocoumon) of the patients a bleeding event occurred during the first year of treatment; no thromboembolic events were reported. Conclusions The quality of anticoagulation treatment was low during the first month of use and leaves room for improvement. After the first month it increased to an acceptable level. However, bleeding events occurred frequently during the first year.
Topics: Acenocoumarol; Administration, Oral; Adolescent; Age Factors; Anticoagulants; Blood Coagulation; Child; Child, Preschool; Drug Monitoring; Female; Guideline Adherence; Hemorrhage; Humans; Infant; International Normalized Ratio; Male; Netherlands; Phenprocoumon; Practice Guidelines as Topic; Practice Patterns, Physicians'; Quality Indicators, Health Care; Retrospective Studies; Thromboembolism; Time Factors; Treatment Outcome
PubMed: 29108090
DOI: 10.1111/jth.13897 -
Oncotarget Jun 2018Oral anticoagulants (OAs) are the recommended drugs to prevent cardiovascular events and recurrence in patients with atrial fibrillation (AF) and cardioembolic stroke.... (Review)
Review
Oral anticoagulants (OAs) are the recommended drugs to prevent cardiovascular events and recurrence in patients with atrial fibrillation (AF) and cardioembolic stroke. We conducted a literature search to review the current state of OAs pharmacogenomics, focusing on Genome Wide Association Studies (GWAs) in patients treated with vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). VKAs: Warfarin, acenocoumarol, fluindione and phenprocoumon have long been used, but their interindividual variability and narrow therapeutic/safety ratio makes their dosage difficult. GWAs have been useful in finding genetic variants associated with VKAs response. The main genes involved in VKAs pharmacogenetics are: and Variants in these genes have been included in pharmacogenetic algorithms to predict the VKAs dose individually in each patient depending on their genotype and clinical variables. DOACs: Dabigatran, apixaban, rivaroxaban and edoxaban have been approved for patients with AF. They have stable pharmacokinetics and do not require routine blood checks, thus avoiding most of the drawbacks of VKAs. Except for a GWAs performed in patients treated with dabigatran, there is no Genome Wide pharmacogenomics data for DOACs. Pharmacogenomics could be useful to predict the better clinical response and avoid adverse events in patients treated with anticoagulants, identifying the most appropriate anticoagulant drug for each patient. Current pharmacogenomics data show that the polymorphisms affecting VKAs or DOACs are different, concluding that personalized medicine based on pharmacogenomics could be possible. However, more studies are required to implement personalized medicine in clinical practice with OA and based on pharmacogenetics of DOACs.
PubMed: 30018749
DOI: 10.18632/oncotarget.25579 -
Clinical Cardiology Jun 2022Atrial fibrillation is the most important risk factor for left atrial appendage (LAA) thrombi, a potentially life-threatening condition. Thrombus resolution may prevent... (Observational Study)
Observational Study
BACKGROUND
Atrial fibrillation is the most important risk factor for left atrial appendage (LAA) thrombi, a potentially life-threatening condition. Thrombus resolution may prevent embolic events and allow rhythm-control strategies, which have been shown to reduce cardiovascular complications.
HYPOTHESIS
There is no significant difference between phenprocoumon and non-Vitamin K-dependent oral anticoagulants (NOACs) in the resolution of LAA-thrombi in a real-world setting.
METHODS
Consecutive patients with LAA-thrombi from June 2013 to June 2017 were included in an observational single-center analysis. The primary endpoint was defined as the resolution of the thrombus. The observational period was 1 year. Resolutions rates in patients on phenprocoumon or NOACs were compared and the time to resolution was analyzed.
RESULTS
We identified 114 patients with LAA-thrombi. There was no significant difference in the efficacy of resolution between phenprocoumon and NOACs (p = .499) at the time of first control which took place after a mean of 58 ± 42.2 (median 48) days. At first control most thrombi were dissolved (74.6%). The analysis after set-time intervals revealed a resolution rate of 2/3 of LAA-thrombi after 8-10 weeks in the phenprocoumon and NOAC groups. After 12 weeks a higher number of thrombi had resolved in the presence of NOAC (89.3%) whereas in the presence of phenprocoumon 68.3% had resolved (p = .046).
CONCLUSION
In this large observational study NOACs were found to be potent drugs for the resolution of LAA-thrombi. In addition, the resolution of LAA-thrombi was found to be faster in the presence of NOAC as compared to phenprocoumon.
Topics: Administration, Oral; Anticoagulants; Atrial Appendage; Atrial Fibrillation; Echocardiography, Transesophageal; Humans; Phenprocoumon; Thrombosis
PubMed: 35373849
DOI: 10.1002/clc.23823