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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 -
Research and Practice in Thrombosis and... Jan 2019Clinicians lack substantiated guidance on when vitamin K antagonist (VKA) treatment should be interrupted preoperatively, especially with regard to phenprocoumon, with...
BACKGROUND
Clinicians lack substantiated guidance on when vitamin K antagonist (VKA) treatment should be interrupted preoperatively, especially with regard to phenprocoumon, with its long half-life of 5.5 days.
OBJECTIVE
To evaluate the efficacy of discontinuing phenprocoumon 5 days preoperatively and determine whether a safe international normalized ratio (INR) was reached.
METHODS
This was a retrospective review of 118 patients using phenprocoumon prior to elective surgery. Preoperative INRs and factors that could potentially influence these values were identified and described. A safe preoperative INR was defined as <1.8.
RESULTS
Of the 118 included patients, 42 patients (35.6%) had an off-target INR. The male sex was significantly and independently associated with an off-target INR (odds ratio [OR] 2.4, 95% confidence interval [CI] 1.022-5.445). A high American Society of Anesthesiologists (ASA) classification was also significantly and independently associated with an off-target INR (OR 2.3, 95% CI: 1.029-5.173).
CONCLUSION
Discontinuation of phenprocoumon 5 days preoperatively resulted in an INR < 1.8 in more than one-third of patients. Individualizing or extending the period of phenprocoumon discontinuation may be a necessary treatment option.
PubMed: 30656280
DOI: 10.1002/rth2.12159 -
Journal of the American Heart... Sep 2018Background Preclinical data have indicated a link between use of vitamin K antagonists ( VKA ) and detrimental effects on vascular structure and function. The objective... (Observational Study)
Observational Study
Background Preclinical data have indicated a link between use of vitamin K antagonists ( VKA ) and detrimental effects on vascular structure and function. The objective of the present study was to determine the relationship between VKA intake and different phenotypes of subclinical cardiovascular disease in the population. Methods and Results Clinical and laboratory data, as well as medical-technical examinations were assessed from 15 010 individuals aged 35 to 74 years during a highly standardized 5-hour visit at the study center of the population-based Gutenberg Health Study. In total, the study sample comprised 287 VKA users and 14 564 VKA nonusers. Multivariable analysis revealed an independent association between VKA intake and stiffness index (β=+2.54 m/s; [0.41/4.66]; P=0.019), ankle-brachial index (β=-0.03; [-0.04/-0.01]; P<0.0001), intima-media thickness (β=+0.03 mm [0.01/0.05]; P=0.0098), left ventricular ejection fraction (β=-4.02% [-4.70/-3.33]; P<0.0001), E/E' (β=+0.04 [0.01/0.08]; P=0.014) left ventricular mass (β=+5.34 g/m [4.26/6.44]; P<0.0001), and humoral markers of cardiac function and inflammation (midregional pro-atrial natriuretic peptide: β=+0.58 pmol/L [0.50/0.65]; P<0.0001; midregional pro-adrenomedullin: β=+0.18 nmol/L [0.14/0.22]; P<0.0001; N-terminal pro B-type natriuretic peptide: β=+1.90 pg/mL [1.63/2.17]; P<0.0001; fibrinogen: β=+143 mg/dL [132/153]; P<0.0001; C-reactive protein: β=+0.31 mg/L [0.20/0.43]; P<0.0001). Sensitivity analysis in the subsample of participants with atrial fibrillation stratified by intake of VKA demonstrated consistent and robust results. Genetic variants in CYP 2C9, CYP 4F2, and VKORC 1 were modulating effects of VKA on subclinical markers of cardiovascular disease. Conclusions These data demonstrate negative effects of VKA on vascular and cardiac phenotypes of subclinical cardiovascular disease, indicating a possible influence on long-term disease development. These findings may be clinically relevant for the provision of individually tailored antithrombotic therapy.
Topics: Adrenomedullin; Adult; Aged; Ankle Brachial Index; Anticoagulants; Asymptomatic Diseases; Atrial Fibrillation; Atrial Natriuretic Factor; C-Reactive Protein; Cardiovascular Diseases; Carotid Intima-Media Thickness; Female; Fibrinogen; Germany; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Phenprocoumon; Protein Precursors; Pulmonary Embolism; Risk Factors; Stroke; Stroke Volume; Vascular Stiffness; Venous Thrombosis; Warfarin
PubMed: 30371151
DOI: 10.1161/JAHA.118.008650 -
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 Sep 2018Patients with end-stage kidney disease requiring maintenance haemodialysis treatment experience a dramatic cardiovascular morbidity and mortality. Due to the high...
Design and rationale of a randomised controlled trial comparing apixaban to phenprocoumon in patients with atrial fibrillation on chronic haemodialysis: the AXADIA-AFNET 8 study.
INTRODUCTION
Patients with end-stage kidney disease requiring maintenance haemodialysis treatment experience a dramatic cardiovascular morbidity and mortality. Due to the high atherosclerotic and arteriosclerotic burden and profound alterations in haemostasis, they frequently suffer and die from both thromboembolic and bleeding events. This is a particular concern in patients on haemodialysis with atrial fibrillation (AF). Controlled trials on the optimal anticoagulation in patients with AF on haemodialysis are not available. The randomised controlled phase IIIb AXADIA-AFNET 8 trial will evaluate the safety and efficacy of the factor Xa inhibitor apixaban in patients with AF requiring haemodialysis.
METHODS AND ANALYSIS
A total of 222 patients will be randomised in an open-labelled, 1:1 design to receive either apixaban 2.5 mg twice daily or dose-adjusted vitamin K antagonist therapy (target international normalised ratio 2.0-3.0). All patients will be treated and followed up for a minimum of 6 months up to a maximum of 24 months. The primary outcome is major or clinically relevant, non-major bleedings or death of any cause. Secondary outcomes include stroke, cardiovascular death and other thromboembolic events, thus exploring the efficacy of apixaban. The first patient was randomised in June 2017.
ETHICS AND DISSEMINATION
The study protocol was approved by the Ethical Committee of the Landesaertzekammer, Westfalen-Lippe and the Medical Faculty of the University of Muenster, Muenster, Germany (reference number: 2016-598 f-A). Written informed consent will be obtained from all patients prior to study participation, including their consent for long-term follow-up. AXADIA-AFNET 8 is an investigator-initiated trial. Sponsor is AFNET, Muenster, Germany. Study findings will be disseminated to Bristol-Myers Squibb, Munich, Germany, and Pfizer, Berlin, Germany, to the participating centres, at research conferences and in peer-reviewed journals.
TRIAL REGISTRATION NUMBERS
NCT02933697,Pre-results.
Topics: Adult; Anticoagulants; Atrial Fibrillation; Female; Germany; Hemorrhage; Humans; Male; Outcome Assessment, Health Care; Phenprocoumon; Pyrazoles; Pyridones; Renal Dialysis; Renal Insufficiency, Chronic; Thromboembolism; Randomized Controlled Trials as Topic
PubMed: 30206088
DOI: 10.1136/bmjopen-2018-022690 -
Blood Nov 2018Warfarin, acenocoumarol, phenprocoumon, and fluindione are commonly prescribed oral anticoagulants for the prevention and treatment of thromboembolic disorders. These...
Warfarin, acenocoumarol, phenprocoumon, and fluindione are commonly prescribed oral anticoagulants for the prevention and treatment of thromboembolic disorders. These anticoagulants function by impairing the biosynthesis of active vitamin K-dependent coagulation factors through the inhibition of vitamin K epoxide reductase (VKOR). Genetic variations in VKOR have been closely associated with the resistant phenotype of oral anticoagulation therapy. However, the relative efficacy of these anticoagulants, their mechanisms of action, and their resistance variations among naturally occurring VKOR mutations remain elusive. Here, we explored these questions using our recently established cell-based VKOR activity assay with the endogenous VKOR function ablated. Our results show that the efficacy of these anticoagulants on VKOR inactivation, from most to least, is: acenocoumarol > phenprocoumon > warfarin > fluindione. This is consistent with their effective clinical dosages for stable anticoagulation control. Cell-based functional studies of how each of the 27 naturally occurring VKOR mutations responds to these 4 oral anticoagulants indicate that phenprocoumon has the largest resistance variation (up to 199-fold), whereas the resistance of acenocoumarol varies the least (<14-fold). Cell-based kinetics studies show that fluindione appears to be a competitive inhibitor of VKOR, whereas warfarin is likely to be a mixed-type inhibitor of VKOR. The anticoagulation effect of these oral anticoagulants can be reversed by the administration of a high dose of vitamin K, apparently due to the existence of a different enzyme that can directly reduce vitamin K. These findings provide new insights into the selection of oral anticoagulants, their effective dosage management, and their mechanisms of anticoagulation.
Topics: Administration, Oral; Anticoagulants; Cell Line; Drug Resistance; Enzyme Inhibitors; Humans; Phenindione; Point Mutation; Vitamin K; Vitamin K Epoxide Reductases; Warfarin
PubMed: 30089628
DOI: 10.1182/blood-2018-05-846592 -
BMC Family Practice Jul 2018Novel oral anticoagulation (NOAC) has been introduced in recent years, but data on use in atrial fibrillation (AF) in primary care setting is scarce. In Germany, General...
BACKGROUND
Novel oral anticoagulation (NOAC) has been introduced in recent years, but data on use in atrial fibrillation (AF) in primary care setting is scarce. In Germany, General Practitioners are free to choose type of oral anticoagulation (OAC) in AF. Our aim was to explore changes in prescription-rates of OAC in German primary care before and after introduction of NOAC on the market.
METHODS
Data of a representative morbidity registration project in primary care in Germany (CONTENT) were analysed. Patients with AF in 2011 or 2014 were included (before and after broad market authorization of NOAC, respectively). We defined three independent groups: patients from 2011 without follow-up (group A), patients from 2014 but without previous record in 2011 (group B) and patients with AF and records in 2011 and 2014 (group C).
RESULTS
2642 patients were included. Group A (n = 804) and B (n = 755) were comparable regarding patient characteristics. 87.3% of group A and 84.8% of group B had CHADS-VASc-Score ≥ 2, indicating a need for oral anticoagulation (OAC). Prescription of OAC increased from 23.1% (n = 186) to 42.8% (n = 323, p < .01) with stable use of vitamin-k-antagonist (22.6-24.9%). NOAC increased from 0.6 to 19.2% (p < .01). Monotherapy with Acetylsalicylic acid (ASA) decreased from 15.3% (n = 123) to 8.2% (n = 62, p < .01). In group C (n = 1083), OAC increased from 35.3 to 55.4% (p < .01), with stable prescription rate of vitamin-k-antagonist (34.4-35.7%). NOAC increased from 0.9 to 21.5% (p < .01).
CONCLUSIONS
In summary, our study showed a significant increase of OAC over time, which is fostered by the use of NOAC but with a stable rate of VKA and a sharp decrease of ASA. Patients on VKA are rarely switched to NOAC, but new patients with AF are more likely to receive NOAC.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Aspirin; Atrial Fibrillation; Cross-Sectional Studies; Dabigatran; Female; Germany; Humans; Male; Middle Aged; Phenprocoumon; Platelet Aggregation Inhibitors; Primary Health Care; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Young Adult
PubMed: 30021509
DOI: 10.1186/s12875-018-0796-4 -
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 -
BMJ Case Reports Feb 2018The cytochrome P450 is a superfamily of isoenzymes that are responsible for the metabolism of many drugs. Significant changes in pharmacokinetics and drug interactions...
The cytochrome P450 is a superfamily of isoenzymes that are responsible for the metabolism of many drugs. Significant changes in pharmacokinetics and drug interactions may be due to induction of hepatic cytochrome P450 enzymes. Rifampicin is a common inducer of CYP3A4. We report a case of a 57-year-old woman who was suspected for endocarditis and therefore treated with rifampicin. Due to previous mechanical aortic valve replacement, she also received phenprocoumon for anticoagulation. Although continuing anticoagulant therapy, antibiotic coadministration led to normal international normalised ratio (INR) level. Fifteen days after the treatment with rifampicin ended, INR returned to therapeutic level.
Topics: Anti-Bacterial Agents; Anticoagulants; Aortic Valve Insufficiency; Cytochrome P-450 Enzyme System; Drug Interactions; Endocarditis; Female; Heart Valve Prosthesis Implantation; Humans; International Normalized Ratio; Middle Aged; Phenprocoumon; Rifampin; Treatment Outcome; Vitamin K
PubMed: 29440136
DOI: 10.1136/bcr-2016-215155 -
Medicine Nov 2017Cystic medial degeneration Erdheim-Gsell is a vascular pathology mainly of the large vessels, which is mostly associated with Marfan syndrome or Ehlers-Danlos syndrome....
RATIONALE
Cystic medial degeneration Erdheim-Gsell is a vascular pathology mainly of the large vessels, which is mostly associated with Marfan syndrome or Ehlers-Danlos syndrome. The clinical findings of this entity are aneurysms of the aorta or large peripheral arteries which usually present in an acute setting due to rupture of an aneurysm.
PATIENT CONCERNS
We present a case of a 43-year-old Caucasian male with histologically proven cystic medial degeneration of the lower limb vessels mimicking peripheral artery occlusive disease. Despite antiplatelet and anticoagulant treatment, the patient suffered multiple vascular stenosis and occlusions.
DIAGNOSES
Multiple arterial stenoses and thromboses leading to peripheral artery occlusive disease caused by cystic medial degeneration Erdheim-Gsell.
INTERVENTIONS
Multiple surgical and endovascular interventions including bypass graft and intra-arterial thrombolysis as well as oral antiplatelet and anticoagulant therapy.
OUTCOME
Despite dual antiplatelet therapy, anticoagulant therapy with rivaroxaban and multiple surgical and endovascular interventions, the patient developed recurrent arterial thromboses. The patient did not suffer further thrombotic events since clopidogrel and phenprocoumon were administered.
LESSONS
Clinical presentation of cystic medial degeneration Erdheim-Gsell mimicking peripheral artery occlusive disease is very unusual. Due to the fragile vessel wall, patients with cystic medial degeneration might have a higher risk to develop arterial thromboses, even under antiplatelet therapy or anticoagulant treatment.
Topics: Adult; Aortic Aneurysm, Thoracic; Arterial Occlusive Diseases; Cysts; Humans; Male; Thrombosis
PubMed: 29381979
DOI: 10.1097/MD.0000000000008782