The children anticoagulation and pharmacogenetics study (CAPS): Developing a dosing algorithm for acencocoumarol in paediatric patients

Background: Dosing of vitamin K antagonists (VKA) in paediatric patients is complex. The large variability in VKA dose requirement asks for elucidating the factors associated with this variability and taking these into account when defining the dose for a patient. For warfarin, paediatric dosing algorithms have been developed, but not for acenocoumarol. Objectives: To develop a dosing algorithm for acenocoumarol in pediatric patients with and without genetic information. Methods: This multicentre retrospective follow-up study was carried out in Dutch anticoagulation clinics and children's hospitals. Patients were selected when they used acenocoumarol for >1 month between January 1995 and December 2014 and were ≤18 years of age. The primary outcome was the mean daily dose during a stable period. A stable period was defined as ≥3 consecutive international normalized ratio measurements within therapeutic range over a period of ≥3 weeks. Clinical information (including height, weight and indication) and saliva samples for genotyping of CYP2C9 (∗2 and ∗3), VKORC1, CYP4F2, CYP2C18 and CYP3A4 (∗1B and ∗22) were collected. Linear regression was used to analyse their association with the log mean stable dose. Results: In total, 175 patients were included of whom 86 patients had a stable period and no missing clinical information (clinical algorithm cohort) and of 80 also genetic information was available (genetic algorithm cohort). The mean age at the stable period was 9 years. The most common indications were Fontan circulation, prosthetic heart valve, deep venous thrombosis and dilated cardiomyopathy. The clinical algorithm, containing body surface area and indication, explained 45.0% of the variability in dose requirement of acenocoumarol. By adding the genotypes of VKORC1, CYP2C18, and CYP2C9∗2/∗3, 61.8% of the variability was explained (genetic algorithm). Conclusions: Clinical factors had the largest impact on the required dose of acenocoumarol in pediatric patients. Including genetic factors in the algorithm, and especially VKORC1, increased this with 16.8%

Incidence of bleeding and thrombotic events in non-institutionalized paediatric patients using warfarin in the united kingdom

Background: Dosing of vitamin K antagonists (VKA) is complex with large inter- and intra-individual variability in patients' required VKA dose. Over- and underdosing can result in bleeding and thrombotic events. The incidence of these events in paediatric patients on warfarin therapy in a European population is unknown. Objectives: To estimate the incidence of bleeding and thrombotic events in warfarin using paediatric patients in the UK and to characterise patients who do or do not experience a bleeding or thrombotic event. Methods: Data were obtained from the UK CPRD in the period between January 1998 and November 2016. Using a cohort design, we identified all patients with ≥1 prescription for warfarin and who were ≤18 years. The date of the first prescription marked the start of the follow-up. Follow-up was classified into periods of warfarin use and non-use. Patients were followed until 19 years of age, death or departure from the practice. The incidence of non-fatal bleeding and thrombotic events was assessed using both information from CPRD and the linked Hospital Episode Statistics (HES). Fatal events were identified usings the linked mortality data from the Office for National Statistics (ONS). For calculating the incidence of thrombotic events only patients without a history of thrombosis were included. Results: In total, 685 patients were identified (median age 15 years, 45.4% female) of whom 372 could be linked to the HES and ONS databases. The incidence of bleeding and thrombotic events during warfarin use was 4.08 and 1.27/100 patient years, respectively. The incidence of bleeding events during non-use was 2.65/100 patient years (relative risk 1.58, 95% confidence interval [0.89-2.80]). Only 2 fatal events occurred, one bleeding and one thrombotic event. Patients with a bleeding event tended to have a higher percentage of INR measurements with a value above 4 (9.4 vs 3.9%) and a lower fraction below 2 (18.4 vs 39.1%) compared to patients without a bleeding event during the whole follow-up. Patients with a thrombotic event showed the opposite trend, a higher percentage of INRs below 2 (45.8 vs 29.5%) and a lower percentage of INRs above 4 (2.7 vs 5.3%). All differences were not statistically significant which maybe due to the small sample size. Conclusions: The incidence of bleeding events was higher than of thrombotic events. The trends in percentages of INRs under and above therapeutic range suggest that keeping the INR within range could decrease the occurence of these events

Primary care diagnostic and treatment pathways in Dutch women with urinary incontinence

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 pointsUrinary 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

The pediatric acenocoumarol dosing algorithm:The Children Anticoagulation and Pharmacogenetics Study

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 patien

Pharmacogenomics in Pediatric Patients: Towards Personalized Medicine

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

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

Effects of age and genetic variations in VKORC1, CYP2C9 and CYP3A4 on the phenprocoumon dose in pediatric patients

AIM: To study the effects of clinical and genetic factors on the phenprocoumon dose requirement in pediatric patients and to develop a dosing algorithm.METHODS: Pediatric patients who used phenprocoumon were invited to participate in a retrospective follow-up study. Clinical information and genotypes of genetic variations in CYP2C9, VKORC1, CYP4F2, CYP2C18 and CYP3A4 were collected and tested with linear regression for association with phenprocoumon dose requirement.RESULTS: Of the 41 patients included in the analysis, age, VKORC1, CYP2C9*2/*3 and CYP3A4*1B were statistically significantly associated with dose requirement, and together explained 80.4% of the variability in phenprocoumon dose requirement.CONCLUSION: Our study reveals that age and genetic variations explain a significant part of the variability in phenprocoumon dose requirement in pediatric patients.</p

Genetic variants associated with methotrexate-induced mucositis in cancer treatment: A systematic review and meta-analysis

Methotrexate (MTX), an important chemotherapeutic agent, is often accompanied with mucositis. The occurrence and severity are unpredictable and show large interindividual variability. In this study, we review and meta-analyze previously studied genetic variants in relation to MTX-induced mucositis. We conducted a systematic search in Medline and Embase. We included genetic association studies of MTX-induced mucositis in cancer patients. A meta-analysis was conducted for single nucleotide polymorphisms (SNPs) for which at least two studies found a statistically significant association. A total of 34 SNPs were associated with mucositis in at least one study of the 57 included studies. Two of the seven SNPs included in our meta-analysis were statistically significantly associated with mucositis: MTHFR c.677C > T (recessive, grade ≥3 vs grade 0–2, OR 2.53, 95 %CI [1.48–4.32], False Discovery Rate[FDR]-corrected p-value 0.011) and MTRR c.66A > G (overdominant, grade ≥1 vs grade 0, OR 2.08, 95 %CI [1.16–3.73], FDR-corrected p-value 0.042)