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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 -
PloS One 2020The health status, health awareness and health behavior of persons with a migration background often differ from the autochthonous population. Little is known about the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The health status, health awareness and health behavior of persons with a migration background often differ from the autochthonous population. Little is known about the proportion of patients with a migration background (PMB) that participate in primary care studies on oral antithrombotic treatment (OAT) in Germany, and whether the quality of their antithrombotic care differs from patients without a migration background. The aim of this paper was to use the results of a cluster-randomized controlled trial (PICANT) to determine the proportion of PMB at different stages of recruitment, and to compare the results in terms of sociodemographic characteristics and antithrombotic treatment.
METHODS
This study used screening and baseline data from the PICANT trial on oral anticoagulation management in GP practices. For this analysis, we determined the proportion of PMB during the recruitment period at stage 1 (screening of potentially eligible patients), stage 2 (eligible patients invited to participate in the trial), and stage 3 (assessment of baseline characteristics of patients participating in the PICANT trial). In addition, we compared patients in terms of sociodemographic characteristics and quality of anticoagulant treatment. Statistical analysis comprised descriptive and bivariate analyses.
RESULTS
The proportion of PMB at each recruitment stage declined from 9.1% at stage 1 to 7.9% at stage 2 and 7.3% at stage 3). A lack of German language skills led to the exclusion of half the otherwise eligible PMB. At stages 1 and 3, PMB were younger (stage 1: 70.7 vs. 75.0 years, p<0.001; stage 3: 70.2 vs. 73.5 years, p = 0.013), but did not differ in terms of gender. The quality of their anticoagulant care was comparable (100.0% vs. 99.1% were receiving appropriate OAT, 94.4% vs. 95.7% took phenprocoumon, or warfarin, and the most recent INR measurement of 60.8% vs. 69.3% was within their individual INR range).
CONCLUSIONS
In the potentially eligible population and among participants at baseline, the quality of anticoagulant care was high in all groups of patients, which is reassuring. To enable the inclusion of more PMB, future primary care research on OAT in Germany should address how best to overcome language barriers. This will be challenging, particularly because the heterogeneity of PMB means the resulting sample sizes for each specific language group are small.
TRIAL REGISTRATION
Current Controlled Trials ISRCTN41847489.
Topics: Aged; Anticoagulants; Demography; Female; Fibrinolytic Agents; Human Migration; Humans; Male; Patient Selection
PubMed: 32176711
DOI: 10.1371/journal.pone.0230297 -
British Journal of Clinical Pharmacology Jul 2020Drug-induced liver injury (DILI) is a heterogenous entity leading to liver damage. We have analysed the frequency, biochemical and histological patterns and clinical...
AIMS
Drug-induced liver injury (DILI) is a heterogenous entity leading to liver damage. We have analysed the frequency, biochemical and histological patterns and clinical courses of DILI cases due to metamizole at our tertiary care centre in Hamburg, Germany.
METHODS
Consecutive patients with DILI who presented to our clinic were analysed retrospectively. Causes of acute hepatitis other than DILI were excluded.
RESULTS
In total, 154 DILI cases were admitted to our centre from 2008 to 2017. After phenprocoumon, metamizole was the second most frequent putative agent causing DILI (23 of all 154 DILI cases, 14,9%). The biochemical pattern on admission of metamizole-induced DILI cases was hepatocellular with median levels of alanine transaminase (779 U/L, 64-3532 U/L) by far exceeding median alkaline phosphatase levels (131 U/L, 42-578 U/L). In 17 of the 23 cases (74%) liver biopsy was performed. Moderate to severe inflammatory histological activity and severe centrilobular necrosis (>30%) was present in 76.5 and 35.3%, respectively. Metamizole was involved in 2 DILI cases progressing to acute liver failure, then receiving liver transplantation and still alive at time of assessment. Our data were supported by re-exposure in 4 patients. Furthermore, a database search for metamizole-induced liver injury in the European Medicines Agency's database identified about 300 reports on suspected metamizole-induced DILI in Europe.
CONCLUSION
Elevation of liver enzymes or acute liver failure are not mentioned in the German drug label of metamizole as potential side effects. Our study reveals that in Germany and Europe, metamizole is a frequent and underrated agent causing DILI.
Topics: Chemical and Drug Induced Liver Injury; Dipyrone; Europe; Germany; Humans; Liver; Retrospective Studies
PubMed: 32080881
DOI: 10.1111/bcp.14254 -
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 Stroke Journal Dec 2019The aim of the present European Stroke Organisation guideline document is to provide clinically useful evidence-based recommendation on reversal of anticoagulant...
The aim of the present European Stroke Organisation guideline document is to provide clinically useful evidence-based recommendation on reversal of anticoagulant activity VKA (warfarin, phenprocoumon and acenocoumarol), direct factor II (thrombin) inhibitors (dabigatran etexilat) and factor-Xa-inhibitors (apixaban, edoxaban and rivaroxaban) in patients with acute intracerebral haemorrhage. The guideline was prepared following the Standard Operational Procedure for a European Stroke Organisation guideline document and according to GRADE methodology. As a basic principle, we defined use of oral anticoagulation pragmatically: oral anticoagulation use is assumed by positive medical history unless relevant anticoagulant activity is regarded unlikely by medical history or has been ruled out by laboratory testing. Overall, we strongly recommend using prothrombin complex over no treatment and fresh-frozen plasma in patients on VKA plus vitamin K. We further strongly recommend using idarucizumab in patients on dabigatran and make a recommendation for andexanet alfa in patients on rivaroxaban and apixaban over no treatment. We make a weak recommendation on using high-dose prothrombin complex concentrate (50 IU/kg) for all patients taking edoxaban and for patients on rivaroxaban or apixaban in case andexanet alfa is not available. We recommend against using tranexamic acid and rFVIIa, outside of trials. The presented treatment recommendations aim to normalise coagulation, there is no or only indirect data on effects on functional outcome or mortality, and only little data from randomised controlled trials.
PubMed: 31903428
DOI: 10.1177/2396987319849763 -
BMC Health Services Research Aug 2019In Germany, patients receiving oral anticoagulation (OAC) are often treated by general practitioners (GPs), and large proportions of patients receive vitamin K... (Randomized Controlled Trial)
Randomized Controlled Trial
Differences in the quality of oral anticoagulation therapy with vitamin K antagonists in German GP practices - results of the cluster-randomized PICANT trial (Primary Care Management for Optimized Antithrombotic Treatment).
BACKGROUND
In Germany, patients receiving oral anticoagulation (OAC) are often treated by general practitioners (GPs), and large proportions of patients receive vitamin K antagonists (VKAs). The quality of OAC in German GP practices, differences between various practices, and improvement potential through implementation of case management, have not yet been investigated satisfactorily. Based on results of a cluster-randomized controlled trial, we aimed to assess whether OAC quality can be improved, any variations between practices exist and determine practice- and patient-level factors.
METHODS
The PICANT trial (2012-2015) was performed in 52 GP practices in Hesse, Germany. Adult patients with long-term indication for OAC received best practice case management in the intervention group. International normalized ratio (INR) values were recorded from anticoagulation passes. The Rosendaal method was used to calculate Time in Therapeutic Range (TTR) at patient level, and mean pooling to obtain center-specific TTR (cTTR) at practice level. The quality of OAC was assessed by TTR and cTTR. Linear model analyses were used to investigate associations between practice-/ patient-level factors and TTR.
RESULTS
Inclusion of 736 patients (49.6% intervention and 50.4% control patients); 690 (93.8%) received phenprocoumon. Within 24 months, the TTR was 75.1% (SD 17.6) in the intervention versus 74.3% (SD 17.8) in the control group (p = 0.670). The cTTR averaged 75.1% (SD 6.5, range: 60.4 to 86.7%) in the intervention versus 74.3% (SD 7.2, range: 52.7 to 85.7%) in the control group (p = 0.668). At practice level, the TTR was significantly lower in practices with a male physician and certification in quality management. At patient level, the TTR was significantly higher in patients with moderate to high compliance, in men, and in patients that performed self-management. The TTR was significantly lower in patients with certain comorbidities, and who were hospitalized.
CONCLUSIONS
The intervention did not effectively improve OAC quality compared to routine care. Quality of INR control was generally good, but considerable variation existed between GP practices. The variability indicates optimization potential in some practices. The demonstrated association between patient-level factors and TTR highlights the importance of considering patient characteristics that may impede achieving high quality therapeutic outcomes.
TRIAL REGISTRATION
ISRCTN registry, ISRCTN41847489 , registered 27 February 2012.
Topics: Administration, Oral; Adult; Anticoagulants; Female; Fibrinolytic Agents; General Practice; Germany; Humans; International Normalized Ratio; Male; Middle Aged; Primary Health Care; Quality of Health Care; Thrombolytic Therapy; Vitamin K
PubMed: 31370840
DOI: 10.1186/s12913-019-4372-y -
BMC Pediatrics Jun 2019Neonatal renal vein thrombosis is a recognised cause of renal and inferior caval vein atresia (IVCA). However, the long-term impact of the condition is underrecognized... (Review)
Review
BACKGROUND
Neonatal renal vein thrombosis is a recognised cause of renal and inferior caval vein atresia (IVCA). However, the long-term impact of the condition is underrecognized with a high burden of morbidity for the patient, especially in adulthood. IVCA has been shown to be an independent risk factor for deep venous thrombosis (DVT) with a high risk of recurrence. The acronym KILT for kidney and inferior vena cava anomaly with leg thrombosis summarizes the pathological situation.
CASE PRESENTATION
We present the case of a 40-year-old patient with pain in the right lower limb resulting from acute thrombophlebitis. No risk factors could be identified. His history was remarkable with two episodes of deep venous thrombosis first of the left, then the right leg 22 years earlier; at that time also, no risk factor was identified. Because of the idiopathic character of that thrombosis, the patient remained on long-term anticoagulation with phenprocoumon. The present thrombophlebitis occurred while the INR was not therapeutic in the preceding weeks. A CT with contrast showed atresia of the inferior vena cava and of the right kidney, and presence of numerous collaterals. A thorough medical history revealed a renal vein thrombosis as a neonate. Anticoagulation was intensified, and stent placement became necessary after a further 2 years.
DISCUSSION AND CONCLUSIONS
KILT syndrome is a rare but underrecognized condition. Complications may arise in young adulthood only, and it is of prime importance to instruct parents of the pediatric patient of the possible consequences of renal vein thrombosis and to assure guidance from the treating physicians throughout adulthood. Diagnosis of IVCA is by CT with contrast or by MRI, and lifelong anticoagulation may be necessary. Since the KILT syndrome is widely underdiagnosed, we challenge the clinicians to keep it in mind when confronted with thrombophlebitis or thrombosis of the young, male and with no other identifiable risk factors for deep vein thrombosis.
Topics: Abbreviations as Topic; Adult; Anticoagulants; Follow-Up Studies; Humans; Infant, Newborn; Kidney; Leg; Male; Pain; Phenprocoumon; Renal Veins; Syndrome; Thrombophlebitis; Time Factors; Tomography, X-Ray Computed; Vascular Malformations; Vena Cava, Inferior; Venous Thrombosis
PubMed: 31170948
DOI: 10.1186/s12887-019-1567-7 -
International Journal of Cardiology.... Jun 2019The risk of thromboembolic events is increased in patients with non-valvular atrial fibrillation (NVAF) and renal impairment. The risk of bleeding events is increased if...
Comparative effectiveness of rivaroxaban versus a vitamin K antagonist in patients with renal impairment treated for non-valvular atrial fibrillation in Germany - A retrospective cohort study.
BACKGROUND
The risk of thromboembolic events is increased in patients with non-valvular atrial fibrillation (NVAF) and renal impairment. The risk of bleeding events is increased if these patients are treated with anticoagulants and further increased in those with active cancer.
METHODS
RELOAD, a retrospective database study, assessed the outcomes of patients with NVAF prescribed rivaroxaban versus phenprocoumon. Here, we present a subgroup analysis evaluating effectiveness and safety of rivaroxaban versus phenprocoumon in patients with NVAF and renal impairment. Analyses were additionally stratified by patients with and without evidence of cancer at baseline.
RESULTS
When using the 'one tablet per day' definition of estimating drug exposure time, the incidence of the primary endpoint of ischaemic stroke was significantly lower in patients (without evidence of cancer at baseline) receiving rivaroxaban 15 mg or 20 mg once daily versus those receiving phenprocoumon (2.40 vs 3.51 events per 100 patient-years, respectively; hazard ratio [HR] = 0.72, 95% confidence interval [CI] 0.55-0.94, = 0.015); with the incidence of the primary safety outcome of intracranial haemorrhage being numerically lower (0.57 vs 0.89 events per 100 patient-years, respectively; HR = 0.66, 95% CI 0.38-1.14, = 0.14). Similar results were observed when using the 'empirical defined daily dose' definition to estimate drug exposure time and when including patients with evidence of cancer.
CONCLUSION
The prescription of rivaroxaban in patients with NVAF and renal impairment was associated with a lower incidence of ischaemic stroke and intracranial haemorrhage versus phenprocoumon in patients without evidence of cancer.
PubMed: 31111087
DOI: 10.1016/j.ijcha.2019.100367 -
BMC Nephrology Apr 2019Calciphylaxis is a life threatening complication in renal patients. Of great importance is the identification of concomitant factors for calciphylaxis. Due to the...
BACKGROUND
Calciphylaxis is a life threatening complication in renal patients. Of great importance is the identification of concomitant factors for calciphylaxis. Due to the variability of clinical presentation the evaluation of such factors may be obscured when calciphylaxis diagnosis is based just on clinical features. We aimed to characterize associated factors only in patients with calciphylaxis proven by histomorphological parameters in addition to clinical presentation.
METHODS
In a single center retrospective study we analyzed 15 patients in an 8 year period from 2008 to 2016. Only patients with clinical features and histomorphological proof of calciphylaxis were included. Criteria for histological diagnosis of calciphylaxis were intimal hyperplasia, micro thrombi or von Kossa stain positive media calcification.
RESULTS
The mean age of patients was 64.8 years. Nine patients (60%) were female; 12 (80%) were obese with a Body-Mass-Index (BMI) > 30 kg/m; 3 (20%) had no renal disease; 12 (80%) had CKD 4 or 5 and 10 (66.7%) had end-stage renal disease (ESRD). One-year mortality in the entire cohort was 73.3%. With respect to medication history, the majority of patients (n = 13 (86.7%)) received vitamin K antagonists (VKA); 10 (66.7%) were treated with vitamin D; 6 (40%) had oral calcium supplementation; 5 (33.3%) had been treated with corticosteroids; 12 (80%) were on proton pump inhibitors (PPI); 13 (86.7%) patients had a clinical proven hyperparathyroidism. Ten (66.7%) patients presented with hypoalbuminemia at diagnosis.
CONCLUSIONS
The evaluation of biopsy proven calciphylaxis demonstrates that especially treatment with vitamin K antagonists and liver dysfunction are most important concomitant factors in development of calciphylaxis. As progression and development of calciphylaxis are chronic rather than acute processes, early use of DOACs instead of VKA might be beneficial and reduce the incidence of calciphylaxis.
Topics: Anticoagulants; Biopsy; Calciphylaxis; Female; Germany; Humans; Incidence; Kidney Failure, Chronic; Liver Diseases; Male; Microvessels; Middle Aged; Mortality; Patient Selection; Phenprocoumon; Retrospective Studies; Risk Factors; Thrombosis; Vascular Calcification
PubMed: 30940121
DOI: 10.1186/s12882-019-1301-6 -
Geriatrics (Basel, Switzerland) Mar 2019Chronic wounds are common in elderly patients, and the majority of them are caused by vascular diseases, such as peripheral arterial occlusive disease (PAD) or chronic...
Chronic wounds are common in elderly patients, and the majority of them are caused by vascular diseases, such as peripheral arterial occlusive disease (PAD) or chronic venous insufficiency. Because of typical signs, these diseases can be usually easily differentiated. However, 10% of chronic wounds are caused by specific rare diseases, such as vasculitis, specific infections, skin cancer, or calciphylaxis. Calciphylaxis is a rare cause of chronic wounds, and it is usually found in patients with end-stage renal disease. In this paper, we describe the case of an 83-year-old woman with a chronic ulcer of the lower leg caused by calciphylaxis.
PubMed: 30889873
DOI: 10.3390/geriatrics4010028