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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 -
Deutsches Arzteblatt International Aug 2013
Topics: Chemical and Drug Induced Liver Injury; Female; Hemorrhage; Hospitalization; Humans; Internal Medicine; Male; Phenprocoumon; Thromboembolism
PubMed: 24069077
DOI: 10.3238/arztebl.2013.0541c -
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 -
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 -
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 -
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 -
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 -
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 -
Journal of Thrombosis and Haemostasis :... May 2012Previous studies have provided contradictory results regarding the interaction between the CYP2C9 and VKORC1 genotypes affecting various outcome measures.
BACKGROUND
Previous studies have provided contradictory results regarding the interaction between the CYP2C9 and VKORC1 genotypes affecting various outcome measures.
OBJECTIVES
We aimed to provide a definite answer regarding the question whether there exists a gene-gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol.
PATIENTS/METHODS
The EU-PACT cohort dataset, which contains data on 624 phenprocoumon and 471 acenocoumarol patients, was used. Patient characteristics, pharmacogenetic data, International Normalized Ratios (INRs) and dosages were available. We investigated whether there was an interaction between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability during the first 180 days of phenprocoumon and acenocoumarol therapy, in addition to the effect of the separate genotypes. The interaction effect was investigated by adding the product term of the CYP2C9 and VKORC1 genotype classes for four different commonly used CYP2C9 classifications to the linear regression model - for the outcome measure maintenance dose - or to the Cox regression models - for the outcome measures time to severe over-anticoagulation and time to achieve stability.
RESULTS
No significant interactions - all P-values above 0.23 for phenprocoumon and 0.30 for acenocoumarol - were observed for all outcome measures.
CONCLUSIONS
There are no interactions between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability for phenprocoumon and acenocoumarol.
Topics: Acenocoumarol; Adult; Aged; Aged, 80 and over; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Blood Coagulation; Cytochrome P-450 CYP2C9; Drug Monitoring; Female; Genotype; Humans; International Normalized Ratio; Linear Models; Male; Middle Aged; Mixed Function Oxygenases; Netherlands; Pharmacogenetics; Phenotype; Phenprocoumon; Proportional Hazards Models; Vitamin K Epoxide Reductases
PubMed: 22409277
DOI: 10.1111/j.1538-7836.2012.04694.x