A Randomized Controlled Trial Comparing Apixaban With the Vitamin K Antagonist Phenprocoumon in Patients on Chronic Hemodialysis: The AXADIA-AFNET 8 Study.

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 CHA2DS2-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]; Pnoninferiority=0.157). Composite primary efficacy outcome events occurred in 10 patients (20.8%) on apixaban and in 15 patients (30.6%) on VKA (P=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.

In atrial fibrillation epilepsy risk differs between oral anticoagulants: active comparator, nested case-control study.

AIMS: Atrial fibrillation (AF) is a risk factor for brain infarction, which can lead to epilepsy. We aimed to investigate whether treatment of AF with direct oral anticoagulants (DOACs) affects the risk of epilepsy in comparison to treatment with the vitamin K antagonist phenprocoumon (PPC). METHODS AND RESULTS: We performed an active comparator, nested case-control study based on the German Pharmacoepidemiological Research Database that includes claims data from statutory health insurance providers of about 25 million persons since 2004. In 2011-17, 227 707 AF patients initiated treatment with a DOAC or PPC, of which 1828 cases developed epilepsy on current treatment with an oral anticoagulant. They were matched to 19 084 controls without epilepsy. Patients with DOAC treatment for AF had an overall higher risk of epilepsy with an odds ratio of 1.39, 95% CI (1.24; 1.55) compared to current PPC treatment. Cases had higher baseline CHA2DS2-VASc scores and more frequently a history of stroke than controls. After excluding patients with ischaemic stroke prior to the diagnosis of epilepsy, the risk of epilepsy was still higher on DOACs than on PPC. In contrast, within a cohort of patients with venous thromboembolism, the risk of epilepsy on treatment with DOACs was less elevated [adjusted odds ratio 1.15, 95% CI (0.98; 1.34)]. CONCLUSION: In patients with AF initiating oral anticoagulation, treatment with a DOAC was associated with an increased risk of epilepsy compared to the vitamin K antagonist PPC. Covert brain infarction may explain the observed elevated risk of epilepsy.

Benefit of Self-Managed Anticoagulation in Patients with Left Ventricular Assist Device.

BACKGROUND: The exact monitoring of the therapeutic-range international normalized ratio (INR) after left ventricular assist device (LVAD) implantation is an important aim to reduce the risk of thrombosis or bleeding complications. Service providers offer a telemedical anticoagulation service (CS). METHODS: We compared LVAD patients using the CS (n = 15) to those who received regular medical care (RMC; n = 15) to investigate if telemedicine supervision increased the INR-specific time in the therapeutic range (TTR) during anticoagulation. All patients received self-management training for phenprocoumon medication according to their INR value. INR values were documented for 12 months. A survey (scale: 1 = not satisfied and 10 = very satisfied) was used to determine patient's satisfaction and psychological well-being. RESULTS: A total of 1,798 INR measurements were analyzed. The TTRRosendaal was higher in patients undergoing RMC (78.1 ± 14.3%) compared with that in patients using the CS (58.3 ± 28.0%, p = 0.03). The patient's satisfaction with the coagulation setting at the beginning of the study (RMC: 6.7 ± 3.1, CS: 7.2 ± 3.0, p = 0.74) and psychological wellbeing (RMC: 6.5 ± 1.9, CS: 6.5 ± 2.7, p = 0.97) were comparable between both groups. CONCLUSION: We found that INR self-management is superior regarding the efficiency of post-LVAD anticoagulation therapy when compared with telemedical (CS)-based INR management in a small study cohort. Intensive training by experienced staff was able to replace CS.

Risk of perioperative bleeding complications in rhegmatogenous retinal detachment surgery: a retrospective single-center study.

PURPOSE: The goal of this study was to analyze the incidence of perioperative bleeding complications in rhegmatogenous retinal detachment. The handling of perioperative anticoagulation during vitreoretinal surgery remains controversial, since the risk of bleeding complications by its continuation has to be balanced against the risk of progression of retinal detachment and the risk of thromboembolic events when anticoagulation is interrupted. Nevertheless, only few studies have investigated the risk of perioperative bleeding complications in an emergency such as retinal detachment surgery. METHODS: We therefore examined the rate of all perioperative hemorrhages and separately the rate of only severe bleedings during vitrectomy, scleral buckling with or without drainage of subretinal fluid (SRD), or combined procedures due to retinal detachment in patients undergoing different types of perioperative anticoagulation including acetylsalicylic acetate (ASA), clopidogrel, heparin, low molecular weight heparin, and phenprocoumon. RESULTS: This retrospective single-center study included 893 patients with primary rhegmatogenous retinal detachment, n = 192 on anticoagulation and n = 701 serving as control without anticoagulation. Our analysis revealed no significantly increased rate of perioperative hemorrhages under anticoagulation with ASA 100 mg (all, 11.4%; severe, 5.0%) or phenprocoumon (all, 11.6%; severe, 2.3%) compared with controls (all, 13.0%; severe, 5.4%). However, frequencies of bleeding complications varied markedly regarding the type of surgical procedure: Scleral buckling plus SRD showed the highest rates of hemorrhages (all, 18.9%; severe, 9.1%) with significant difference (P < 0.001) compared with scleral buckling without SRD (all, 3.8%; severe, 0.6%) and vitrectomy (all, 9.2%; severe, 1.5%), respectively. Furthermore, subretinal bleeding was the most common type of perioperative hemorrhage. CONCLUSIONS: The data suggest not to stop ASA therapy prior to vitreoretinal surgery. Furthermore, we found no evidence of an increased risk for perioperative bleedings in patients under anticoagulation with vitamin-k antagonists with an INR within the sub-therapeutic range. SRD during scleral buckling procedure should be avoided as possible and regardless of any type of anticoagulation.

Vitamin K Antagonist (Phenprocoumon) and Subarachnoid Hemorrhage: A Single-Center, Matched-Pair Analysis.

BACKGROUND: Demographic changes are leading to an aging society with a growing number of patients relying on anticoagulation, and vitamin K antagonists (VKA) are still widely used. As mortality and functional outcomes are worse in case of VKA-associated hemorrhagic stroke, phenprocoumon treatment seems to be a negative prognostic factor in case of subarachnoid hemorrhage (SAH). The purpose of this study was to analyze whether phenprocoumon treatment does worsen the outcome after non-traumatic SAH. METHODS: All patients treated for non-traumatic SAH between January 2007 and December 2016 in our institution were retrospectively analyzed. After exclusion of patients with anticoagulant or antiplatelet treatment other than phenprocoumon, we analyzed 1040 patients. Thirty-three patients (3%) of those were treated with continuous phenprocoumon. In total, 132 out of all 1007 patients without anticoagulant treatment of the remaining patients were matched as control group (ratio = 1:4). RESULTS: Patients with phenprocoumon treatment were significantly older (66.5 years vs. 53.9 years; p < .0001), and admission status was significantly more often poor (66.7% vs. 41.8%, p = .007) compared to all patients without anticoagulant treatment. Further, bleeding pattern and rates of early hydrocephalus did not differ. Matched-pair analysis revealed a significant higher rate of angio-negative SAH in the study group (p = .001). Overall rates of hemorrhagic or thromboembolic complications did not differ (21.4% vs. 18.8%; NS) but were more often fatal, and 30-day mortality rate was significantly higher in the phenprocoumon group than in patients of the matched-pair control group (33% vs. 24%; p < .001). 30% of the phenprocoumon group and 37% of the matched-pair control group reached favorable outcome. However, poor outcome was strong associated with the reason for phenprocoumon treatment. CONCLUSION: Patients with phenprocoumon treatment at the time of SAH are significantly older, admission status is worse, and 30-day mortality rates are significantly higher compared to patients without anticoagulant treatment. However, outcome at 6 months did not differ to the matched-pair control group but seems to be strongly associated with the underlying cardiovascular disease. Treatment of these patients is challenging and should be performed on an interdisciplinary base in each individual case. Careful decision-making regarding discontinuation and bridging of anticoagulation and close observation is mandatory.

Perioperative bridging of vitamin K antagonist treatment in patients with atrial fibrillation: only a very small group of patients benefits.

AIMS: Bridging anticoagulation in atrial fibrillation (AF) patients who need to interrupt vitamin K antagonists for procedures is a clinical dilemma. Currently, guidelines recommend clinicians to take the stroke and bleeding risk into consideration, but no clear thresholds are advised. To aid clinical decision making, we aimed to develop a model in which periprocedural bridging therapy is compared with withholding anticoagulation in AF patients, for several bleeding and stroke risk groups. METHODS AND RESULTS: A model was developed to simulate both a bridge and a non-bridge cohort, using simulated international normalized ratio (INR) values for patients on warfarin, acenocoumarol, and phenprocoumon. For both clinical strategies, stroke and bleeding risks were included and outcomes were stratified by CHA2DS2-VASc or CHADS2 and HAS-BLED groups. Quality-adjusted life expectancy was the main outcome considered. Our analyses show bridging to only be beneficial for patients with HAS-BLED scores equal or lower to 2 and with CHA2DS2-VASc scores of 6 or higher. For patients using acenocoumarol bridging may be beneficial starting at a CHA2DS2-VASc score of 7. Post-procedural time to therapeutic INR has a significant influence on the results: no significant benefit of bridging was found for patients reaching therapeutic INR values within 5 days. CONCLUSION: When deciding whether to bridge anticoagulation, clinicians should consider the patient's individual stroke and bleeding risk, while also considering the patient's post-procedural INR management. In practice, only a small subset of patients is expected to benefit from bridging anticoagulation treatment.

Shorter hospital stays in epistaxis patients with atrial fibrillation when taking rivaroxaban or apixaban versus phenprocoumon.

Patients taking oral anticoagulants (OACs) currently represent one-third of all patients treated for epistaxis and an upward trend is expected. New direct oral anticoagulants (DOACs) have been on the market for approximately 10 years. DOACs are favoured over Vitamin K-Antagonists (VKAs) in the current guidelines. There are barely studies that investigate the impact of DOACs on patients with epistaxis. A retrospective study was performed analysing all patients who had stationary treatment for epistaxis from 01.01.2011 to 01.01.2018 in a tertiary care centre. In a total of 466 patients, 46.1% were on OACs. The main indication was atrial fibrillation (AF, 67.4%).The number of DOACs taken surpassed that of the VKAs during the past 2 years. The length of hospital stay was significantly longer in the phenprocoumon group (3 ± 0.2 days) in comparison to both the rivaroxaban (2.3 ± 0.1) and the apixaban (2.2 ± 0.1) groups (p = 0.005). Posterior epistaxis occurred more frequently in the phenprocoumon group (10.8%) than in the rivaroxaban (0%) and apixaban (0%) groups (p = 0.03). A correlation between CHA2DS2-VASc score (risk score for apoplexy in patients with AF, p = 0.01), HAS-BLED score (score for assessment of major bleeding in patients taking anticoagulants with AF, p = 0.006), and length of hospital stay (p = 0.002) with recurrence of epistaxis was found. Shorter hospital stays and exclusively anterior bleeding was noted in AF patients taking rivaroxaban and apixaban, whereas AF patients taking phenprocoumon stayed in hospital longer and had more posterior bleeding.

Phenprocoumon based anticoagulation is an underestimated factor in the pathogenesis of calciphylaxis.

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/m2; 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.

Thrombophlebitis hiding under a KILT - case report on 40 years long-term follow-up of neonatal renal vein thrombosis.

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.

Comparative risks of bleeding, ischemic stroke and mortality with direct oral anticoagulants versus phenprocoumon in patients with atrial fibrillation.

PURPOSE: The pivotal trials for stroke prevention in non-valvular atrial fibrillation (NVAF) compared rivaroxaban, dabigatran, and apixaban with warfarin, as did most claims-based studies. Comparisons with phenprocoumon, the most frequently used vitamin K antagonist (VKA) in Germany, are scarce. METHODS: Risk of bleeding, ischemic stroke, and all-cause mortality in patients with NVAF were analyzed using data for 2010 to 2014 from a large German claims database. New users of oral anticoagulants from January 2012 to December 2013 were included and observed over 1 year. Baseline characteristics were adjusted using propensity score matching and logistic regression. Several sensitivity analyses were carried out. RESULTS: Fifty-nine thousand four hundred forty-nine rivaroxaban, 23,654 dabigatran, 4894 apixaban, and 87,997 matched phenprocoumon users were included. Adjusted hazard ratios (95% confidence intervals) compared with phenprocoumon were as follows: hospitalized bleedings: rivaroxaban 1.04 (0.97; 1.11), dabigatran 0.87 (0.77; 0.98), and apixaban 0.65 (0.50; 0.86); ischemic stroke: rivaroxaban 1.05 (0.94; 1.17), dabigatran 1.14 (0.96; 1.35), and apixaban 1.84 (1.20; 2.84); all-cause mortality: rivaroxaban 1.17 (1.11; 1.22), dabigatran 1.04 (0.95; 1.13), and apixaban 1.14 (0.97; 1.34). CONCLUSIONS: With rivaroxaban, no significant differences were observed compared to phenprocoumon with regard to hospitalized bleedings or ischemic strokes. Dabigatran was associated with fewer bleedings and a similar risk of ischemic strokes compared to phenprocoumon. Apixaban was also associated with fewer bleedings but was unexpectedly associated with more ischemic strokes, possibly reflecting selective prescribing. The association of rivaroxaban with higher all-cause mortality unrelated to bleedings or strokes has been described previously but remains to be explained.

Novel oral anticoagulants in primary care in patients with atrial fibrillation: a cross-sectional comparison before and after their introduction.

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 CHA2DS2-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.

Statin use decreases coagulation in users of vitamin K antagonists.

PURPOSE: The purpose of the study is to determine the immediate and long-term effect of statins on coagulation in patients treated with vitamin K antagonists (VKAs). METHODS: We selected patients on VKAs of two Dutch anticoagulation clinics who initiated treatment with a statin between 2009 and 2013. Patients who initiated or stopped concomitant drugs that interact with VKAs or were hospitalised during follow-up were excluded. The VKA dosage (mg/day) after statin initiation was compared with the last VKA dosage before the statin was started. Immediate and long-term differences in VKA dosage (at 6 and 12 weeks) were calculated with a paired student t test. RESULTS: Four hundred thirty-five phenprocoumon users (mean age 70 years, 60 % men) and 303 acenocoumarol users (mean age 69 years, 58 % men) were included. After start of statin use, the immediate phenprocoumon dosage was 0.02 mg/day (95 % CI, 0.00 to 0.03) lower. At 6 and 12 weeks, these phenprocoumon dosages were 0.03 (95 % CI, 0.01 to 0.05) and 0.07 mg/day (95 % CI, 0.04 to 0.09) lower as compared with the dosage before first statin use. In acenocoumarol users, VKA dosage was 0.04 mg/day (95%CI, 0.01 to 0.07) (immediate effect), 0.10 (95 % CI, 0.03 to 0.16) (at 6 weeks), and 0.11 mg/day (95 % CI, 0.04 to 0.18) (after 12 weeks) lower. CONCLUSIONS: Initiation of statin treatment was associated with an immediate and long-term minor although statistically significant decrease in VKA dosage in both phenprocoumon and acenocoumarol users, which suggests that statins may have anticoagulant properties.

Atypical Femoral Fractures-Ongoing and History of Bone-Specific Therapy, Concomitant Diseases, Medications, and Survival.

Although atypical femoral fractures (AFFs) are generally rare events; several studies have indicated a potential link between AFF and long-term bone-specific therapies (BSTs). The aim of this study was to analyze the frequency of AFF and potential associations with prior or ongoing BST. A total of 8851 Caucasian female and male patients with de novo hip fractures treated in the largest Austrian level 1 trauma center from 2000 to 2013 were selected. Of the total, 194 patients with a de novo low-traumatic subtrochanteric or shaft fractures were identified: 35 atypical and 159 typical fractures. Of these patients, concomitant diseases, medication, previous fractures, and survival data were retrieved and analyzed. Female patients in both groups were significantly older. The median survival was significantly shorter in patients with AFF (9 vs 18 months; p < 0.0001). Cardiovascular disease, sarcopenia, chronic kidney disease, type 2 diabetes, smoking (past or current history), and prevalent fragility fractures were more frequent in AFF patients, as well as the concomitant use of phenprocoumon, furosemide, and sulfonylurea. Although the number of patients with current BST was less in (14.5%) both groups, more patients in the AFF group were previously treated with BST (71% vs 49%; p = 0.016), and they received these therapies for a longer time period. A combination of severe comorbidities, long-term pharmaceutical therapies, and a history of previous or ongoing BST was associated with an increased individual risk for AFF.

PPARA gene and phenprocoumon: a new predictor of response variability.

Phenprocoumon is an anticoagulant used for thromboembolic disorder prophylaxis metabolized mainly by CYP3A4. However, polymorphisms in this gene did not explain the observed variability. PPARA (peroxisome proliferator-activated receptor-α) is a nuclear receptor that, among others, influences CYP3A4 gene expression. The aim of this study was to determine whether PPARA gene polymorphisms and the CYP3A4*22 allele are associated with phenprocoumon dose variability. A total of 198 patients on a stable dose of phenprocoumon were included in the study. Genotyping was performed by allele discrimination using standardized TaqMan assays. Differences between the average phenprocoumon dose and genotypes/haplotypes were assessed by analysis of variance and multiple linear regression analyses. Patients with the PPARA rs4253728A allele needed higher phenprocoumon doses. However, the effect size (3%) of this association was small. The CYP3A4*22 allele was not associated with the dose of phenprocoumon. As this is the first report of an association between PPARA gene polymorphisms and phenprocoumon dose, future studies are warranted to confirm these results.

Quality of oral anticoagulation with phenprocoumon in regular medical care and its potential for improvement in a telemedicine-based coagulation service--results from the prospective, multi-center, observational cohort study thrombEVAL.

BACKGROUND: The majority of studies on quality of oral anticoagulation (OAC) therapy with vitamin K-antagonists are performed with short-acting warfarin. Data on long-acting phenprocoumon, which is frequently used in Europe for OAC therapy and is considered to enable more stable therapy adjustment, are scarce. In this study, we aimed to assess quality of OAC therapy with phenprocoumon in regular medical care and to evaluate its potential for optimization in a telemedicine-based coagulation service. METHODS: In the prospective observational cohort study program thrombEVAL we investigated 2,011 patients from regular medical care in a multi-center cohort study and 760 patients from a telemedicine-based coagulation service in a single-center cohort study. Data were obtained from self-reported data, computer-assisted personal interviews, and laboratory measurements according to standard operating procedures with detailed quality control. Time in therapeutic range (TTR) was calculated by linear interpolation method to assess quality of OAC therapy. Study monitoring was carried out by an independent institution. RESULTS: Overall, 15,377 treatment years and 48,955 international normalized ratio (INR) measurements were analyzed. Quality of anticoagulation, as measured by median TTR, was 66.3% (interquartile range (IQR) 47.8/81.9) in regular medical care and 75.5% (IQR 64.2/84.4) in the coagulation service (P <0.001). Stable anticoagulation control within therapeutic range was achieved in 63.8% of patients in regular medical care with TTR at 72.1% (IQR 58.3/84.7) as compared to 96.4% of patients in the coagulation service with TTR at 76.2% [(IQR 65.6/84.7); P = 0.001)]. Prospective follow-up of coagulation service patients with pretreatment in regular medical care showed an improvement of the TTR from 66.2% (IQR 49.0/83.6) to 74.5% (IQR 62.9/84.2; P <0.0001) in the coagulation service. Treatment in the coagulation service contributed to an optimization of the profile of time outside therapeutic range, a 2.2-fold increase of stabile INR adjustment and a significant decrease in TTR variability by 36% (P <0.001). CONCLUSIONS: Quality of anticoagulation with phenprocoumon was comparably high in this real-world sample of regular medical care. Treatment in a telemedicine-based coagulation service substantially improved quality of OAC therapy with regard to TTR level, frequency of stable anticoagulation control, and TTR variability. TRIAL REGISTRATION: ClinicalTrials.gov, unique identifier NCT01809015, March 8, 2013.

Novel factor xa inhibitor for the treatment of cerebral venous and sinus thrombosis: first experience in 7 patients.

BACKGROUND AND PURPOSE: Thrombosis of cerebral veins and sinus (cerebral venous thrombosis) is a rare stroke pathogenesis. Pharmaceutical treatment is restricted to heparin and oral anticoagulation with vitamin K antagonists (VKAs). METHODS: Between January 2012 and December 2013, we recorded data from our patients with cerebral venous thrombosis. The modified Rankin scale was used to assess clinical severity; excellent outcome was defined as modified Rankin scale 0 to 1. Recanalization was assessed on follow-up MR angiography. Patients were then divided into 2 treatment groups: phenprocoumon (VKA) and a novel factor Xa inhibitor. Clinical and radiological baseline data, outcome, recanalization status, and complications were retrospectively compared. RESULTS: Sixteen patients were included, and 7 were treated with rivaroxaban. Overall outcome was excellent in 93.8%, and all patients showed at least partial recanalization. No statistical significant differences were found between the groups, except the use of heparin before start of oral anticoagulation (P=0.03). One patient in the VKA and 2 patients in the factor Xa inhibitor group had minor bleeding (P=0.55) within the median (range) follow-up of 8 months (5-26). CONCLUSIONS: Factor Xa inhibitor showed a similar clinical benefit as VKA in the treatment of cerebral venous thrombosis. Further systematic prospective evaluation is warranted.

Preadmission oral anticoagulant treatment and clinical outcome among patients hospitalized with acute stroke and atrial fibrillation: a nationwide study.

BACKGROUND AND PURPOSE: Preadmission oral anticoagulant treatment (OAT) has been linked with less severe stroke and a better outcome in patients with atrial fibrillation. However, the existing studies have methodological limitations and have, with one exception, not included hemorrhagic strokes. We performed a nationwide historic follow-up study using data from population-based healthcare registries to assess the effect of preadmission OAT on stroke outcomes further. METHODS: We identified 11 356 patients with atrial fibrillation admitted to hospital with acute stroke (including ischemic stroke and intracerebral hemorrhage) between 2003 and 2009. Propensity score-matched analyses were used to compare stroke severity (Scandinavian Stroke Scale score) and mortality among 2175 patients with preadmission OAT and 2175 patients without preadmission OAT. RESULTS: A total of 2492 (21.9%) patients received OAT at the time of their stroke. Preadmission OAT was associated with a lower risk of severe stroke (Scandinavian Stroke Scale score at time of admission, <30 point; propensity score-matched odds ratio, 0.74; 95% confidence interval, 0.63-0.86) and lower 30-day mortality rate (propensity score-matched adjusted odds ratio, 0.83; 95% confidence interval, 0.71-0.98). CONCLUSIONS: Only a minority of hospitalized patients with acute stroke with atrial fibrillation received OAT at the time of stroke. Preadmission OAT was associated with less severe stroke and lower 30-day mortality rate in a propensity score-matched analysis.

Beliefs about medicines in Dutch acenocoumarol and phenprocoumon users.

AIMS: Adherence to the generally complex regimen of coumarin derivatives is vital in order to keep patients in the adequate International Normalized Ratio range. Patients' beliefs about medicines are associated with the level of therapy adherence. Our first aim was to assess beliefs about coumarins. Secondly, we compared the beliefs about coumarins with the beliefs about other cardiovascular drugs. METHODS: The Beliefs about Medicines Questionnaire was used to assess medication beliefs. The questionnaire was completed by new users of coumarins indicated for venous thromboembolism or atrial fibrillation. A necessity score and a concerns score were calculated for all patients. The analyses were repeated for users of antihypertensive drugs or statins (not using coumarins). RESULTS: Three hundred and twenty patients were included in the analysis of the beliefs about coumarins. The mean necessity score was 15.3, the concerns score 12.3 and the necessity-concerns differential 3.0. Patients with venous thromboembolism (n = 71) had higher necessity scores than patients with atrial fibrillation (n = 249; 16.8 vs. 14.9, P < 0.001). The mean necessity score in 493 users of other cardiovascular drugs was 16.1, the concerns score 13.5 and the necessity-concerns differential 2.6. The necessity score was higher in chronic cardiovascular drug users (n = 192) than in new users (n = 301; 17.9 vs. 14.9, P < 0.001). CONCLUSIONS: Coumarin users score higher on the necessity scale than on the concerns scale, which is also the case in users of other cardiovascular drugs. Patients with atrial fibrillation have a less positive attitude towards these drugs than patients with venous thromboembolism, and could therefore benefit more from specific attention.