It is well known that drug responses differ among patients with regard to dose requirements, efficacy, and adverse drug reactions (ADRs). The differences in drug responses are partially explained by genetic variation. This paper highlights some examples of areas in which the different responses (dose, efficacy, and ADRs) are studied in children, including cancer (cisplatin), thrombosis (vitamin K antagonists), and asthma (long-acting β2 agonists). For childhood cancer, the replication of data is challenging due to a high heterogeneity in study populations, which is mostly due to all the different treatment protocols. For example, the replication cohorts of the association of variants in TPMT and COMT with cisplatin-induced ototoxicity gave conflicting results, possibly as a result of this heterogeneity. For the vitamin K antagonists, the evidence of the association between variants in VKORC1 and CYP2C9 and the dose is clear. Genetic dosing models have been developed, but the implementation is held back by the impossibility of conducting a randomized controlled trial with such a small and diverse population. For the long-acting β2 agonists, there is enough evidence for the association between variant ADRB2 Arg16 and treatment response to start clinical trials to assess clinical value and cost effectiveness of genotyping. However, further research is still needed to define the different asthma phenotypes to study associations in comparable cohorts. These examples show the challenges which are encountered in pediatric pharmacogenomic studies. They also display the importance of collaborations to obtain good quality evidence for the implementation of genetic testing in clinical practice to optimize and personalize treatment.

To cite this article: Maagdenberg H, Bierings MB, van Ommen CH, van der Meer FJM, Appel IM, Tamminga RYJ, de Boer A, Maitland-van der Zee AH. Characteristics and quality of oral anticoagulation treatment in pediatric patients in the Netherlands based on the CAPS cohort. 2018; 16: 116-24. J Thromb Haemost Essentials• The knowledge of quality and safety of acenocoumarol and phenprocoumon use in children is limited.• We used data from a multicenter retrospective followup 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.

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Objective To investigate how GPs manage women with urinary incontinence (UI) in the Netherlands and to assess whether this is in line with the relevant Dutch GP guideline. Because UI has been an underreported and undertreated problem for decades despite appropriate guidelines being created for general practitioners (GPs). Design Retrospective cohort study. Setting Routine primary care data for 2017 in the Netherlands. Subjects We included the primary care records of women aged 18–75 years with at least one contact registered for UI, and then extracted information about baseline characteristics, diagnosis, treatment, and referral to pelvic physiotherapy or secondary care. Results In total, 374 records were included for women aged 50.3 ± 15.1 years. GPs diagnosed 31.0%, 15.2%, and 15.0% women with stress, urgency, or mixed UI, respectively; no diagnosis of type was recorded in 40.4% of women. Urinalysis was the most frequently used diagnostic test (42.5%). Education was the most common treatment, offered by 17.9% of GPs; however, no treatment or referral was reported in 15.8% of cases. As many as 28.7% and 21.7% of women were referred to pelvic physiotherapy and secondary care, respectively. Conclusion Female UI is most probably not managed in line with the relevant Dutch GP guideline. It is also notable that Dutch GPs often fail to report the type of UI, to use available diagnostic approaches, and to provide appropriate education. Moreover, GPs referred to specialists too often, especially for the management of urgency UI. Key points Urinary incontinence (UI) has been an underreported and undertreated problem for decades. Despite various guidelines, UI often lies outside the GPs comfort zone. •According to this study: general practitioners do not treat urinary incontinence according to guidelines. •The type of incontinence is frequently not reported and diagnostic approaches are not fully used. •We believe that increased awareness will help improve treatment and avoidable suffering.

To cite this article: Maagdenberg H, Bierings MB, van Ommen CH, van der Meer FJM, Appel IM, Tamminga RYJ, le Cessie S, Swen JJ, van der Straaten T, de Boer A, Maitland-van der Zee AH. The pediatric acenocoumarol dosing algorithm: the Children Anticoagulation and Pharmacogenetics Study. J Thromb Haemost 2018; https://doi.org/10.1111/jth.14211. Essentials• A pediatric pharmacogenetic dosing algorithm for acenocoumarol has not yet been developed.• We conducted a multicenter retrospective follow-up study in children in the Netherlands.• Body surface area and indication explained 45.0% of the variability in dose requirement.• Adding the genotypes of VKORC1, CYP2C9 and CYP2C18 to the algorithm increased this to 61.8%. Summary. Background:The large variability in dose requirement of vitamin K antagonists is well known. For warfarin, pediatric dosing algorithms have been developed to predict the correct dose for a patient; however, this is not the case for acenocoumarol. Objectives: To develop dosing algorithms for pediatric patients receiving acenocoumarol with and without genetic information. Methods: The Children Anticoagulation and Pharmacogenetics Study was designed as a multicenter retrospective follow-up study in Dutch anticoagulation clinics and children's hospitals. Pediatric patients who used acenocoumarol between 1995 and 2014 were selected for inclusion. Clinical information and saliva samples for genotyping of the genes encoding cytochrome P450 (CYP) 2C9, vitamin K epoxide reductase complex subunit 1 (VKORC1), CYP4F2, CYP2C18 and CYP3A4 were collected. Linear regression was used to analyze their association with the log mean stable dose. A stable period was defined as three or more consecutive International Normalized Ratio measurements within the therapeutic range over a period of ≥ 3 weeks. Results: In total, 175 patients were included in the study, of whom 86 had a stable period and no missing clinical information (clinical cohort; median age 8.9 years, and 49% female). For 80 of these 86 patients, genetic information was also available (genetic cohort). The clinical algorithm, containing body surface area and indication, explained 45.0% of the variability in dose requirement of acenocoumarol. After addition of the VKORC1, CYP2C9, and CYP2C18 genotypes to the algorithm, this increased to 61.8%. Conclusions: These findings show that clinical factors had the largest impact on the required dose of acenocoumarol in pediatric patients. Nevertheless, genetic factors, and especially VKORC1, also explained a significant part of the variability.

Our study reveals that age and genetic variations explain a significant part of the variability in phenprocoumon dose requirement in pediatric patients.

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IntroductionAs part of the cyclic Appropriate Care programme of the National Health Care Institute in the Netherlands, a systematic analysis of hearing health care is taking place. Parties in hearing health care are actively involved throughout the entire process. This abstract focuses on lessons learned from the cooperation as a HTA body with a diverse group of stakeholders.MethodsWe carried out an in-depth analysis for the patient journey of both children and adults with ear complaints or hearing impairment. Different kinds of information were included in the analyses, including claims data, quantitative and qualitative research, analyses of (international) guidelines and patient information. A range of strategies were used to co-operate and interact with patient organizations, hearing health care professionals, institutes/hospitals and insurance companies.ResultsClose collaboration between the project team and patient organizations turned out to be effective to comprehend patient’ perspectives. Data analyses were often found to be challenging in hearing health care, as the reimbursement data lacked sufficient information. In several cases, building bridges between parties, but also in relation to our HTA body was needed. Conclusions from the analyses were being shared and discussed with a panel of involved stakeholders, leading to support, but not always consensus on potential room for improvement. An internal review process turned out to be helpful in sharing experiences on effective multi-stakeholder management.ConclusionsWe believe that the process did influence the way stakeholders think about the appropriate use of the different available treatment options. Building bridges, and combining different perspectives from patient organizations, health-care professionals and insurance companies is necessary in a cyclic approach. The cyclic appropriate Care programme proved to be a constructive approach for collaboration with stakeholders.