Pharmacogenetic Aspects and Drug Interactions in Anticoagulation Therapy with Coumarins

The mysterious ability of blood to clot has fascinated people over millennia. In the beginning of the 20th century, the mechanisms became better understood. In 1922, the development of hemorrhagic disease in cattle caused by mouldy sweet clover was described by Schofield. The absence or delay of blood clotting was correlated to a greatly diminished quantity of prothrombin. This discovery remained unnoticed until twenty years later the ‘hemorrhagic agent’ was identified as dicoumarol, 3,3-methylene-bis. It was promptly made available for clinical studies and already one year later first experiences on the effectiveness in deep vein thrombosis as well as its hemorrhagic complications were published. From the coumarin derivates synthesized, the most potent one was warfarin, an acronym for the Wisconsin Alumni Research Foundation (WARF). As it was used successfully to fight rats, its name may also contribute to that ‘warfare’. It was patented in 1948 and is since then the most frequently used coumarin worldwide. In 1929, Dam observed haemorrhage and markedly prolonged coagulation times in chickens fed with diets from which fat was completely extracted. He concluded that the substance whose absence in the diet was responsible for the coagulation and bone growth pathologies should be a new fat-soluble vitamin which he named vitamin K (“Koagulation”). For the discovery of vitamin K and the purification, characterization and synthesis of the vitamin, Dam and Doisy were awarded the Nobel Prize in Medicine in 1943. It was known then empirically that vitamin K reversed the bleeding problem of mouldy sweet clover poisoning. However, it took three more decades until the vitamin K cycle was proposed in 1974. After another three decades, in 2004, the complex biochemical relationship between vitamin K, its epoxide, and coumarins was enlightened by identifying the VKORC1 gene. This gene encodes the protein which is the target of the coumarins. Genetically mutated variants of the gene have been shown to cause warfarin-resistance phenotypes as well as pathogenic deficiency of all vitamin K-dependent coagulation factors

Drug Burden Index and Cognitive and Physical Function in Aged Care Residents:A Longitudinal Study

Objectives: Anticholinergic/antimuscarinic and sedative medications (eg, benzodiazepines) have been found to be associated with poorer cognitive and physical function and mobility impairment in older age. However, previous studies were mostly conducted among community-dwelling older individuals and had often a cross-sectional design. Accordingly, our aim was to examine longitudinal associations between cumulative exposure to anticholinergic and sedative medications and cognitive and physical function among residents from aged care homes. Design: Longitudinal study. Setting and Participants: A total of 4624 residents of Dutch aged care homes of whom data were collected between June 2005 and April 2014. Methods: Outcome measures were collected with the Long-Term Care Facilities assessment from the international Residential Assessment Instrument (interRAI-LTCF) and included the Cognitive Performance Scale, the Activities of Daily Living (ADL) Hierarchy scale, a timed 4-meter walk test, distance walked, hours of physical activity, and days being outside. Cumulative exposure to anticholinergic and sedative medications was calculated with the Drug Burden Index (DBI), a linear additive pharmacological dose-response model. Associations were examined with linear mixed models to take the potential dependence of observations into account (ie, data were collected at repeated assessment occasions of residents who were clustered in aged care homes). Analyses were adjusted for sex, age, dementia, comorbidity (neurological, psychiatric, cardiovascular, oncological, and pulmonary), fractures, depressive symptoms, and medications excluded from the DBI. Results: We observed significant longitudinal associations between a higher DBI and poorer ADLs, fewer hours of physical activity, and fewer days being outside. We found no significant longitudinal association between a higher DBI and poorer cognitive function. Conclusions and Implications: Over time, cumulative exposure to anticholinergic and sedative medications is associated with poorer physical but not cognitive function in aged care residents. Careful monitoring of aged care residents with high cumulative anticholinergic and sedative medication exposure is needed

Allergic rhinitis self-care advice in community pharmacies: A simulated patient study

Background: Pharmacists and pharmacy assistants can support consumers by identifying minor ailments and providing evidence-based advice about treatment options. In the Netherlands, advice is based on national minor ailment guidelines and structured WWHAM questions (Who, What, How long, Action, Medication). Objectives: To study whether pharmacy assistants provide guideline-compliant advice for allergic rhinitis based on WWHAM and condition-specific questions (When and Familiarity) and their association with appropriate self-care advice. Methods: A retrospective study of the assessments of simulated patient (SP) visits regarding one condition- and two symptom-based cases of allergic rhinitis in Dutch community pharmacies. Pharmacies that participated in 2014, 2016 and 2018 were selected. SPs documented their observations of the problem analysis, dispensing and client interaction on a standardized scoresheet. Dispensing of an oral antihistamine according to the guideline recommendation was considered as the correct outcome. Chi-square tests were used to analyze differences in scores for problem analysis of pharmacies with correct and incorrect advice provision in 2014 and 2018. Predictors for correct outcome were identified by univariate and multivariate logistic regression analysis. Results: Data from 673 pharmacies were available for all three years. In 2014 and 2018, problems were presented as a symptom (running nose), and 41.2% and 21.1% of pharmacies dispensed an antihistamine. For the condition-based problem (allergy) in 2016, 96.0% of participating pharmacies dispensed an antihistamine. Both in 2014 and 2018, each additional problem analysis question increased the odds ratio of providing correct advice. Questions asked about 'hay fever symptoms', 'medication', 'when symptoms occurred', and 'familiar symptoms' were significant predictors of correct advice provision. Conclusions: Most pharmacies provided appropriate advice for a condition-based request but less than half of them provided appropriate advice for a symptom-based request. More questions asked was associated with an increased chance of providing correct advice. Addition of condition-specific questions may improve the WWHAM-method

Pharmaceutical Care Network Europe definition of quality indicators for pharmaceutical care: a systematic literature review and international consensus development

Background Over the past 40 years, the tasks of pharmacists have shifted from logistic services to pharmaceutical care (PhC). Despite the increasing importance of measuring quality of care, there is no general defnition of Quality Indicators (QIs) to measure PhC. Recognising this, a working group in a European association of PhC researchers, the Pharmaceutical Care Network Europe (PCNE), was established in 2020. Aim This research aimed to review existing definitions of QIs and develop a definition of QIs for PhC. Method A two-step procedure was applied. Firstly, a systematic literature review was conducted to identify existing QI definitions that were summarised. Secondly, an expert panel, comprised of 17 international experts from 14 countries, participated in two surveys and a discussion using a modifed Delphi technique to develop the definition of QIs for PhC. Results A total of 182 QI definitions were identifed from 174 articles. Of these, 63 QI definitions (35%) cited one of fve references as the source. Sixteen aspects that construct QI definitions were derived from the identifed definitions. As a result of the Delphi study, the panel reached an agreement on a one-sentence defnition of QIs for PhC: “quality indicators for pharmaceutical care are validated measurement tools to monitor structures, processes or outcomes in the context of care provided by pharmacists”. Conclusion Building upon existing defnition of QIs, an international expert panel developed the PCNE definition of QIs for PhC. This definition is intended for universal use amongst researchers and healthcare providers in PhC

Barriers and facilitators for providing self-care advice in community pharmacies: a qualitative study

BACKGROUND: Community pharmacies are easily accessible for self-care advice. Guidelines for providing self-care advice were introduced in several countries, including the Netherlands in the 1990s. Previous studies have indicated room for improvement in self-care advice in daily pharmacy practice. AIM: To identify barriers and facilitators for providing self-care advice. METHOD: Semi-structured interviews were conducted face-to-face or online with pharmacists and pharmacy assistants using a topic guide based on the Theoretical Domains Framework. The interviews were audio-recorded and transcribed verbatim. The transcripts were deductively analysed to identify barriers and facilitators for self-care counselling. COREQ guidelines were followed. RESULTS: In total, 13 pharmacists and 12 pharmacy assistants were interviewed to reach data saturation. In general, most themes addressed by pharmacists and pharmacy assistants belonged to similar domains. The following domains were frequently mentioned: environmental context and resources (e.g. priority for prescription drugs, privacy, collaboration with general practitioners, access to patients' records), intentions (providing reliable advice), skills (communication, decision-making), knowledge (ready guideline knowledge), beliefs about consequences (patient safety), social influences (patient awareness of pharmacist role), reinforcement (lack of reimbursement for relatively time-consuming advice). CONCLUSION: This study identifies barriers and facilitators for evidence-based self-care advice. Pharmacists should first support pharmacy assistants by helping them keep their knowledge and skills up to date and creating suitable pharmacy preconditions to facilitate improvements in self-care counselling. Second, collaboration with general practitioners regarding minor ailments should be improved

Filled prescriptions of age-related contraindicated drugs in children: a one-year nationwide cohort study in the Netherlands

Background Children are still prescribed age contraindicated drugs, but information about the number and type of these drugs dispensed for children in the Netherlands is limited. Objective To determine the incidence and prevalence of contraindicated drugs that were dispensed for the use by children. Setting The study was conducted in the Netherlands with routinely collected data from 95% of all community pharmacies. Method We performed a one-year nationwide observational study where all patients aged 17 years or younger who have received at least one prescription in 2016 were included. Contraindicated drugs were selected, according to the 5th level of ATC code, using different information sources. Main outcome measure The proportion of (newly) contraindicated drugs that were dispensed to children. Results In total, 3.9% of all children received at least one drug that was contraindicated for their age. The highest percentage of contraindicated drugs that was dispensed, was observed in patients aged 1–2 years and 13–17 years (7.0 and 5.7%, respectively) and the percentage of contraindicated drugs that were dispensed was higher in female than in male patients (4.3 and 3.6%, respectively; p value < 0.001). Conclusion The results of this study show that a substantial percentage of children received a drug that was conta-indicated for their age, and it happes more in female than in male patients. Furthermore, the information about this type of contraindications is limited and inconsistent

Long-term exposure to anticholinergic and sedative medications and cognitive and physical function in later life

Background: Anticholinergic and sedative medications are frequently prescribed to older individuals. These medications are associated with short-term cognitive and physical impairment, but less is known about long-term associations. We therefore examined over twenty years whether cumulative exposure to these medications was related to poorer cognitive and physical functioning. Methods: Older adult participants of the Longitudinal Aging Study Amsterdam (LASA) were followed from 1992-2012. On 7 measurement occasions, cumulative exposure to anticholinergic and sedative medications was quantified with the Drug Burden Index (DBI), a linear additive pharmacological dose-response model. Cognitive functioning was assessed with the Mini Mental State Examination (MMSE), Alphabet Coding Task (ACT, 3 trials), Auditory Verbal Learning Test (AVLT, learning and retention condition), and Raven Colored Progressive Matrices (RCPM, 2 trials). Physical functioning was assessed with the Walking Test (WT), Cardigan Test (CT), Chair Stands Test (CST), Balance Test (BT), and self-reported Functional Independence (FI). Data were analyzed with linear mixed models adjusted for age, education, sex, living with a partner, BMI, depressive symptoms, co-morbidities (cardiovascular disease, diabetes, cancer, COPD, osteoarthritis, CNS diseases), and prescribed medications. Results: Longitudinal associations were found of the DBI with poorer cognitive functioning (less items correct on the 3 ACT trials, AVLT learning condition, and the 2 RCPM trials) and with poorer physical functioning (longer completion time on the CT, CST, and lower self-reported FI). Conclusions: This longitudinal analysis of data collected over 20 years, showed that higher long-term cumulative exposure to anticholinergic and sedative medications was associated with poorer cognitive and physical functioning

SERIES:eHealth in primary care. Part 2: Exploring the ethical implications of its application in primary care practice

Background: eHealth promises to increase self-management and personalised medicine and improve cost-effectiveness in primary care. Paired with these promises are ethical implications, as eHealth will affect patients' and primary care professionals' (PCPs) experiences, values, norms, and relationships.Objectives: We argue what ethical implications related to the impact of eHealth on four vital aspects of primary care could (and should) be anticipated.Discussion: (1) EHealth influences dealing with predictive and diagnostic uncertainty. Machine-learning based clinical decision support systems offer (seemingly) objective, quantified, and personalised outcomes. However, they also introduce new loci of uncertainty and subjectivity. The decision-making process becomes opaque, and algorithms can be invalid, biased, or even discriminatory. This has implications for professional responsibilities and judgments, justice, autonomy, and trust. (2) EHealth affects the roles and responsibilities of patients because it can stimulate self-management and autonomy. However, autonomy can also be compromised, e.g. in cases of persuasive technologies and eHealth can increase existing health disparities. (3) The delegation of tasks to a network of technologies and stakeholders requires attention for responsibility gaps and new responsibilities. (4) The triangulate relationship: patient-eHealth-PCP requires a reconsideration of the role of human interaction and 'humanness' in primary care as well as of shaping Shared Decision Making.Conclusion: Our analysis is an essential first step towards setting up a dedicated ethics research agenda that should be examined in parallel to the development and implementation of eHealth. The ultimate goal is to inspire the development of practice-specific ethical recommendations

Diagnosis of acute cystitis in primary care: symptom-based versus urinalysis-based diagnosis

AIM: This study aimed to provide insight into the congruity of acute cystitis (AC) diagnosis in women, measured both by the Acute Cystitis Symptom Score (ACSS) questionnaire and urine test(s). BACKGROUND: The ACSS questionnaire was developed as a self-administering tool for assessing urinary symptoms, quality of life (QoL) and treatment outcomes in healthy, nonpregnant female patients. METHODS: This prospective observational cohort study compared AC diagnosis based on the questionnaire with a GP diagnosis based on dipstick/dipslide test(s). ACSS questionnaire form A (typical and differential symptoms, QoL and relevant conditions) was filled in by the patient group, women suspected for AC visiting a GP practice with a urine sample, and the reference group, women visiting a community pharmacy for any medication. Analyses were performed assuming that the GP diagnosis based on urine test(s) was correct. Divergent result(s) of urine test(s) and ACSS questionnaire were analysed for scores of all individual questionnaire domains. Statistical analyses included descriptive statistics and the positive predictive value (PPV) and the negative predictive value (NPV) of the ACSS questionnaire and the urine test(s). FINDINGS: In the patient group, 59 women were included, 38 of whom a GP positively diagnosed for AC. The reference group included 70 women. The PPV of the ACSS questionnaire was 77.3%, and the NPV was 73.3%. Analysis of patient data for divergent results showed that differential symptoms, QoL and relevant conditions explained false-positive and false-negative results. Revised results (most probable diagnosis) based on this analysis showed a PPV and NPV of 88.6% and 73.3% for the ACSS questionnaire and 100% and 76.2% for the urine test(s). For use in primary care, a reduction in false-positive and false-negative results can be achieved by including scores for differential symptoms, QoL and relevant conditions, alongside a total typical symptoms score of 6 or higher