Comparative effectiveness of factor Xa non-vitamin K antagonist oral anticoagulants versus phenprocoumon in patients with non-valvular atrial fibrillation.

BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) have largely supplanted vitamin K antagonists (VKAs) for oral anticoagulation in non-valvular atrial fibrillation (NVAF). However, data on the real-world effectiveness of NOACs vs. phenprocoumon, a VKA widely used in Germany, are limited. The RELOADED study aimed to compare effectiveness of factor Xa NOACs and phenprocoumon in NVAF in clinical practice. METHODS: Patients who started on a factor Xa NOAC or phenprocoumon for NVAF during the study period were enrolled from the Institute for Applied Healthcare Research Berlin. Patients were followed from first prescription until the end of exposure or available data. Primary outcomes were analyzed by Cox proportional hazard regression models and included ischemic stroke and systemic embolism for effectiveness, and intracranial hemorrhage (ICH) for safety. Subgroups of interest were patients with diabetes and patients with renal impairment. RESULTS: The total study population was 64,920; 36.3% of patients initiated phenprocoumon, 34.4% initiated rivaroxaban, 25.0% apixaban, and 4.4% edoxaban. Treatment with phenprocoumon is associated with a similar risk of ischemic stroke/systemic embolism as treatment with rivaroxaban or apixaban; while rivaroxaban (adjusted hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.43-0.75) and apixaban (adjusted HR 0.43, 95% CI 0.31-0.6) were associated with a lower risk of ICH compared to phenprocoumon in NVAF patients. The use of rivaroxaban and apixaban was associated with a lower risk of developing kidney failure in patients with diabetes or renal impairment in comparison to those treated with phenprocoumon. CONCLUSION: The factor Xa NOACs rivaroxaban and apixaban demonstrated similar effectiveness and lower rates of ICH compared with phenprocoumon in this study.

Quality of Anticoagulation With Phenprocoumon and Warfarin in Left Ventricular Assist Device Patients: A Multicenter Study.

VISUAL ABSTRACT: of key results. INR, international normalized ratio; TTR, time in therapeutic range; PTR, percentage of tests in range; HRAE, hemocompatibility-related adverse event; FFUV, first follow-up visit; GIB, gastrointestinal bleeding; HR, hazard ratio.http://links.lww.com/ASAIO/A961.

Vitamin-K-antagonist phenprocoumon versus direct oral anticoagulants in patients with atrial fibrillation: a real-world analysis of German claims data.

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.

The influence of excessive consumption of liquorice on phenprocoumon (Marcumar®): a case report.

Here, the case of a 92-year-old female patient, who was diagnosed with atrial fibrillation and treated with phenprocoumon (Marcumar®), is reported. Pre-existing comorbidities were arterial hypertension, coronary heart disease, diabetes mellitus type 2, mild senile dementia and renal insufficiency. Despite treatment with phenprocoumon (Marcumar®), the patient experienced an ischaemic stroke. Her measured international normalized ratio (INR)-values during the months before the stroke were within the therapeutic range of 2-3, then suddenly decreased to 1.25. A retrospective inquiry failed to identify any significant changes in behaviour or therapy adherence, other than the consumption of 1.5 kg (3.3 lb) of hard-boiled candy liquorice in the days leading up to the stroke. The sudden decrease in INR-values may be explained by the influence of liquorice and its compounds on the pharmacokinetics of phenprocoumon (Marcumar®). In this context, the most important factors are the susceptibility of vitamin K antagonists to nutrition or metabolic irregularities, the influence of liquorice on the function of isoenzymes of the cytochrome P450 family that may lead to reduced bioavailability of phenprocoumon, and the influence of liquorice on peroxisome proliferator-activated receptor alpha transactivation.

Factor IX p.A37V mutation causes severe bleeding in a patient with phenprocoumon therapy.

BACKGROUND: Bleeding is the most common complication of oral anticoagulants, due to inadequate dosing. CASE PRESENTATION: This report describes the clinical course of a patient who developed severe bleeding under therapy with phenprocoumon, despite an INR in the lower therapeutic range. Strikingly, aPTT was prolonged, while factor IX activity was significantly reduced. Acquired hemophilia was excluded, due to missing detection of inhibitors. Finally, sequencing part of the factor IX gene including nucleotide position c.110 revealed a hemizygous factor IX mutation c.110C > T p (Ala37Val). CONCLUSIONS: In rare cases, missense mutations in factor IX propeptide are associated with severe bleeding complications. The substitution of alanin at position 37 to either valin or threonin (Ala37Val or Ala37Thr) leads to hypersensitivity to vitamin k antagonists.

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 traumatic intracranial haemorrhage is increased in older people exposed to oral anticoagulation with phenprocoumon.

BACKGROUND: Hospital admissions resulting from traumatic intracranial haemorrhages (TIH) in older people are increasing. There are concerns regarding an increased risk of a TIH in people taking oral anticoagulants (OAC) like phenprocoumon. AIMS: The aim of this study was to estimate the incremental risk of a TIH associated with OAC in older people. Furthermore, this study explored differences in risk according to functional status. METHODS: The study took data from a large German health insurance provider and combined hospital diagnoses with data regarding drug dispensing to estimate rates of a TIH in people with and without exposure to phenprocoumon. Analyses were stratified by sex and by severe functional impairment as disclosed by the long-term care insurance provider. RESULTS: Overall, exposure to OAC resulted in 2.7 times higher rates of TIH. People with severe functional impairment had a higher baseline risk of TIH than people without severe functional impairment. However, the incremental risk in those exposed to OAC was similar among people with and without severe functional impairment (standardised incidence rate difference 15.73 (95% CI 7.84; 23.61) and 12.10 (95% CI 9.63; 14.57) per 10,000 person-years, respectively). CONCLUSIONS: OAC increases the risk of TIH considerably. The incremental risk of TIH in those exposed to OAC is comparable between people with and without severe functional impairment. The presence of severe functional impairment per se should not exclude such patients from the potential benefits of OAC. For now, the prescription should be personalized based on individual fall risk factors and risk-taking behaviour.

Multistate methodology improves risk assessment under time-varying drug intake-a new view on pregnancy outcomes following coumarin exposure.

PURPOSE: Observational cohort studies are essential to evaluate the risk of adverse pregnancy outcomes associated with drug intake. Besides left truncation and competing events, it is crucial to account for the time-dynamic pattern of drug exposure. In fact, potentially harmful medications are often discontinued, which might affect the outcome. Ignoring these challenges may lead to biased estimation of drug-related risks highlighting the need for adequate statistical techniques. METHODS: We reanalyze updated data of a recently published study provided by the German Embryotox pharmacovigilance institute. The aim of the study was to quantify the effect of discontinuation of vitamin K antagonist phenprocoumon on the risk of spontaneous abortion. RESULTS: We outline multistate methodology as a powerful method removing bias in probability estimation inherent to commonly used crude proportions. We incorporate time-dependent discontinuation and competing pregnancy outcomes as separate states in a multistate model, which enables the formulation of hazard-based Cox proportional hazard models and the application of so-called landmark techniques. Results show that early discontinuation of phenprocoumon substantially reduces the risk of spontaneous abortion, which is of great importance for both pregnant women and treating physicians. CONCLUSIONS: An adequate handling of discontinuation times is essential when analyzing the risk of spontaneous abortion. The proposed concepts are not restricted to pregnancy outcome studies but have broad usage in other fields of epidemiology. Our nontechnical report may provide guidance for the design and analysis of future studies. Example code is provided.

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.

Management of Oral Anti-Coagulation in Patients with Heart Failure-Insights from the ThrombEVAL Study.

Patients with heart failure (HF) are frequently anti-coagulated with vitamin K-antagonists (VKAs). The use of long-acting VKA may be preferable for HF patients due to higher stability of plasma concentrations. However, evidence on phenprocoumon-based oral anti-coagulation (OAC) therapy in HF is scarce. The aim of this study was to assess the impact of the presence of HF on quality of phenprocoumon-based OAC and the subsequent clinical outcome. Quality of OAC therapy and the incidence of adverse events were analysed in a cohort of regular care (n = 2,011) from the multi-centre thrombEVAL study program (NCT01809015) stratified by the presence of HF. To assess the modifiability of outcome, results were compared with data from individuals receiving specialized care for anti-coagulation (n = 760). Overall, the sample comprised of 813 individuals with HF and 1,160 subjects without HF in the regular care cohort. Quality of OAC assessed by time in therapeutic range (TTR) was 66.1% (47.8%/82.8%) for patients with HF and 70.6% (52.1%/85.9%) for those without HF (p = 0.0046). Stratification for New York Heart Classification (NYHA)-class demonstrated a lower TTR with higher NYHA classes: TTRNYHA-I 69.6% (49.4%/85.6%), TTRNYHA-II 66.5% (50.1%/82.9%) and TTRNYHA-≥III 61.8% (43.1%/79.9%). This translated into a worse net clinical benefit outcome for HF (hazard ratio [HR] 1.63 [1.31/2.02]; p < 0.0001) and an increased risk of bleeding (HR 1.40 [1.04/1.89]; p = 0.028). Management in a specialized coagulation service resulted in an improvement of all, TTR (∆+12.5% points), anti-coagulation-specific and non-specific outcome of HF individuals. In conclusion, HF is an independent risk factor for low quality of OAC therapy translating into an increased risk for adverse events, which can be mitigated by specialized care.

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.

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.

Is rivaroxaban associated with higher morbidity and mortality in patients with traumatic head injuries? A retrospective cohort study comparing rivaroxaban, no anticoagulation, and phenprocoumon.

OBJECTIVES: The use of new anticoagulants potentially carries the risk of increased intracranial bleeding, but there is a lack of evidence. The aim of this study was to investigate whether the morbidity and mortality differs in head trauma patients depending on the type of anticoagulation. PATIENTS AND METHODS: A retrospective cohort study was conducted in 2009-2014. Based on sex, age, and Glasgow-Coma Scale (GCS), patients that received rivaroxaban were matched to two control groups, one that received no anticoagulant and another one that received phenprocoumon. The primary outcome was mortality. Among others, secondary outcome variables were the length of stay (LOS) at the hospital and presence of an intracranial injury. RESULTS: Sixty-nine patients (23 patients per group) were analyzed. The characteristics of patients did not differ significantly across groups. There were no significant differences between groups for the primary and secondary outcomes. Two patients died in the rivaroxaban group (one of them likely due to head trauma), while one patient died in the phenprocoumon group (likely not due to head trauma), and no patient died in the no anticoagulatoin group (p = 0.36). The LOS at the hospital was similar (5.0, 4.0, and 5.0 days; p = 0.94). An intracranial injury was observed in a similar number of patients in all groups (n = 11, n = 10, and n = 8; p = 0.75). CONCLUSION: Although limited in size, this study did not observe significant outcome differences in patients with traumatic head injuries, who received rivaroxaban, no anticoagulant or phenprocoumon. Although not significant, the only death likely due to head trauma in the study occurred in the rivaroxaban group. Larger studies are needed before clinical application of these findings.

Influence of antithrombotic agents on recurrence rate and clinical outcome in patients operated for chronic subdural hematoma / Influencia de los agentes anti-trombóticos en la tasa de recidiva y el resultado clínico en los pacientes operados de hematoma subdural crónico

Introduction: Chronic subdural hematoma (cSDH) is a common pathology encountered in neurosurgical practice, especially in elderly patients, who frequently require antithrombotic agents. The aim of this study was to investigate the influence of antithrombotic agents on recurrence rates and clinical outcomes in patients operated for cSDH. Methods: A cohort of patients operated for cSDH at one center during a 5 years period was analyzed retrospectively. Presenting symptoms, coagulation testing, history of antithrombotic agents and comorbidities were obtained from the patient charts. The standard neurosurgical procedure was a single burr hole under local anesthesia with insertion of a subdural drainage. Questionnaires and telephone interviews were used to assess the clinical outcome using the modified Rankin Scale (mRS). Good outcome was defined as mRS 0 to 3 and poor outcome as mRS 4 to 6. Results: 201 patients with cSDH underwent initial surgical treatment and were enrolled in the study. The median follow-up was 81 weeks. 41 patients (20.4%) were on antiplatelet drug and 43 (21.4%) were on phenprocoumon. A recurrent hematoma required surgery in 37 patients (18.4%). A poor outcome was seen in 36 patients (17.9%). Each of older age and administration of phenprocoumon at admission was an independent risk factor predictive of poor outcome, (p = 0.001 and p = 0.031, respectively)) Administration of antithrombotic agents had no impact on hematoma recurrence. Conclusion: Administration of phenprocoumon and older age might increase the risk of poor outcome in patients with cSDH. Neither the administration of phenprocoumon nor antiplatelet drug influenced the recurrence rate of subdural hematoma in our patient cohort

Introducción: El hematoma subdural crónico (HSC) es una enfermedad común en la práctica neuro-quirúgica, especialmente en pacientes mayores, quienes requieren con frecuencia agentes anti-trombóticos. El objetivo de este estudio fue investigar la influencia de los agentes anti-trombóticos en las tasas de recidiva y los resultados clínicos en los pacientes operados de HSC. Métodos: Se analizó retrospectivamente una cohorte de pacientes operados de HSC en un único centro, durante un periodo de 5 años. Se obtuvieron de las historias de los pacientes los síntomas de presentación, las pruebas de coagulación, el historial de agentes anti-trombóticos y las comorbilidades. El procedimiento quirúrgico estándar consistió en una trepanación bajo anestesia local, con inserción de un drenaje subdural. Se utilizaron cuestionarios y entrevistas telefónicas para valorar el resultado clínico mediante la Escala de Rankin modificada (mRS). El resultado favorable se definió como el valor de 0 a 3 de mRS, y el resultado desfavorable el valor de 4 a 6. Resultados: Doscientos uno pacientes con HSC fueron sometidos a tratamiento quirúrgico inicial, y fueron incluidos en el estudio. El seguimiento medio fue de 81 semanas. A 41 pacientes (20,4%) se les administró tratamiento anti-plaquetario y a 43 (21,4%) fenprocumón. El hematoma recurrente requirió cirugía en 37 pacientes (18,4%). Se observaron resultados desfavorables en 36 pacientes (17,9%). La avanzada edad y la administración de fenprocumón al ingreso resultaron factores predictivos independientes del resultado desfavorable (p = 0,001 y p = 0,031, respectivamente). La administración de agentes antitrombóticos no tuvo impacto sobre la recidiva del hematoma. Conclusión: La administración de fenprocumón y la edad avanzada pueden incrementar el riesgo de resultado desfavorable en los pacientes con HSC. Ni la administración de fenprocumón ni la de fármacos anti-plaquetarios influyeron en la tasa de hematomas subdurales en nuestra cohorte de pacientes

Problems in anticoagulation of a patient with antibiotic treatment for endocarditis: interaction of rifampicin and vitamin K antagonists.

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.

Meta-Analysis of Genotype-Guided Versus Standard Dosing of Vitamin K Antagonists.

Vitamin K antagonist (VKA) is a commonly prescribed anticoagulant with a narrow therapeutic window. Genetic polymorphisms account for high VKA dosage variability. Hence, we performed an updated meta-analysis of all randomized clinical trials (RCTs) comparing genotype-guided VKA versus standard dosing algorithms. We conducted a systematic search of electronic databases from inception to October 2017 for all RCTs. The primary outcome was the percentage of time in therapeutic range (TTR). Secondary outcomes were international normalized ratio >4, major and all bleeding events, thromboembolism, adverse and serious adverse events, and all-cause mortality. We calculated the weighted mean difference for the primary outcome and risk ratio (RR) for secondary outcomes using a random-effect model. We included 20 RCTs and analyzed a total of 5,980 adult patients. Our pooled analysis showed greater improvement in TTR for the genotype-guided group in comparison with the standard group (mean difference 3.41%, 95% confidence interval [CI] 0.71 to 6.10, p = 0.01). In addition, there were significant reductions in major and all bleeding events ((RR 0.35, 95% CI 0.20 to 0.63, p = 0.0004) and (RR 0.79, 95% CI 0.66 to 0.95, p = 0.01), respectively). However, there were no significant differences between the groups for international normalized ratio >4 (RR 0.89, 95% CI 0.80 to 1.00, p = 0.06), thromboembolism (RR 0.81, 95% CI 0.56 to 1.17, p = 0.25), serious adverse events (RR 0.79, 95% CI 0.61 to 1.03, p = 0.08), any adverse events (RR 0.94, 95% CI 0.88 to 1.01, p = 0.07), or all-cause mortality (RR 0.73, 95% CI 0.32 to 1.66, p = 0.46). In conclusion, genotype-guided VKA dosing can improve the TTR and reduce the risk for bleeding episodes, in comparison with standard dosing algorithms.

Non-vitamin K-dependent oral anticoagulants have a positive impact on ischaemic stroke severity in patients with atrial fibrillation.

Aims: Several studies showed reduced stroke severity in patients with atrial fibrillation (AF) if the international normalized ratio (INR) was ≥ 2 at stroke onset. There are no respective data for non-vitamin K-dependent oral anticoagulants (NOACs). The aim of this study was to compare the impact of NOAC or phenprocoumon intake on stroke severity. Methods and results: In this single-centre observational study, 3669 patients with acute ischaemic stroke were retrospectively analysed regarding AF status and medication immediately before admission. Using multivariable regression, we analysed the association of pre-admission anticoagulation with severe stroke (National Institutes of Health Stroke Scale score ≥ 11) on admission and poor outcome at discharge (modified Rankin scale score > 2). Before the index stroke, 655 patients had known AF and a CHA2DS2-VASc score ≥ 2. While 325 (49.6%) patients were anticoagulated, 159 (24.3%) were prescribed a NOAC and 75 (11.5%) phenprocoumon patients had an INR ≥ 2 on admission. Compared with AF patients without medical stroke prevention, an INR ≥ 2 [OR 0.23 (95% CI 0.10-0.53)] or NOAC intake [OR 0.48 (95% CI 0.27-0.86)] were associated with a lower probability of severe stroke after adjustment for confounders, while an INR < 2 [OR 0.62 (95% CI 0.33-1.16)] was not. Adjusted odds ratios for poor functional outcome at hospital discharge were 0.47 (95% CI 0.27-0.84) for NOAC patients, 0.33 (95% CI 0.17-0.65) for INR ≥ 2 and 0.61 (95% CI 0.32-1.16) for INR < 2. Conclusion: NOAC intake before stroke did reduce the probability of severe stroke on hospital admission and poor functional outcome at hospital discharge as similarly demonstrated for phenprocoumon patients with an INR ≥ 2 on admission.

Characteristics and quality of oral anticoagulation treatment in pediatric patients in the Netherlands based on the CAPS cohort.

Essentials The knowledge of quality and safety of acenocoumarol and phenprocoumon use in children is limited. We used data from a multicenter retrospective follow-up study in children in the Netherlands. The quality of anticoagulation control in the first month of use was low, but improved thereafter. No thromboembolic events occurred, however bleeding events occurred in 1-3 out of 10 patients. SUMMARY: Background The use of vitamin-K antagonists in pediatric patients is rare and information on the quality and safety of treatment with acenocoumarol and phenprocoumon is limited. Objectives To assess the quality, safety and effectiveness during the first year of acenocoumarol and phenprocoumon treatment in pediatric patients in the Netherlands. Methods The Children Anticoagulation and Pharmacogenetics Study (CAPS) was designed as a multicenter retrospective follow-up study. Patients who used acenocoumarol or phenprocoumon at an age of ≤ 18 years, were selected from four pediatric hospitals and one anticoagulation clinic in the Netherlands. The quality of treatment was assessed by calculating the percentage of time in therapeutic INR range (TTR) for the first month and for every 3 months of use during the first year of treatment. Effectiveness and safety were assessed by the number of thromboembolic and bleeding events. Results In total, 213 patients participated, of whom 187 (155 acenocoumarol; 32 phenprocoumon) were included in this analysis. The mean TTR was 47.0% and 51.4% in the first month of use for acenocoumarol and phenprocoumon, respectively. After the first 3 months the mean TTR for both VKAs was above 64%. In 14.6% (acenocoumarol) and 31.3% (phenprocoumon) of the patients a bleeding event occurred during the first year of treatment; no thromboembolic events were reported. Conclusions The quality of anticoagulation treatment was low during the first month of use and leaves room for improvement. After the first month it increased to an acceptable level. However, bleeding events occurred frequently during the first year.