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Background In older patients, the choice between kidney transplantation (KT) and dialysis may be complicated because of a high prevalence of comorbidities and geriatric syndromes. Ideally, this decision-making process focusses on older patients’ outcome priorities, which frequently include functional, psychological, and quality of life (QOL)-related outcomes. Purpose This systematic review aims to summarize functional, psychological (including cognition), and QOL-related outcomes after start of kidney replacement therapy (KRT) in older adults. Methods We searched PubMed and Embase for research that investigated change in these variables after start of KRT in patients aged ≥ 60 years. Data were extracted using the summary measures reported in the individual studies. Risk of bias was assessed with the ROBINS-I tool. Results Sixteen observational studies (prospective n = 9, retrospective n = 7; KT-recipients n = 3, dialysis patients n = 13) were included. The results show that QOL improves in the majority of the older KT recipients. After start of dialysis, QOL improved or remained stable for most patients, but this seems less prevalent than after KT. Functional status decreases in a substantial part of the older dialysis patients. Furthermore, the incidence of serious fall injuries increases after start of dialysis. Nutritional status seems to improve after start of dialysis. Conclusion The interpretability and comparability of the included studies are limited by the heterogeneity in study designs and significant risk of bias in most studies. Despite this, our overview of functional, psychological (including cognition), and QOL-related outcomes is useful for older adults and their clinicians facing the decision between KT and dialysis.

Introduction Major barriers in deprescribing are the ambivalence of patients, resistance to change, and poor acceptance of alternative treatments. Objective To investigate older patients’ beliefs, understanding and knowledge, satisfaction with medicine use, health outcome priorities, their attitude toward deprescribing, and to identify associated patient factors. Methods This multi-center cross-sectional, semistructured survey study involved older outpatients (70 years of age and older) with polypharmacy. The survey comprised three validated questionnaires: Beliefs about Medicines Questionnaire, Patients’ Attitudes Towards Deprescribing questionnaire, and the Health Outcome Prioritization tool, with additional questions about understanding and satisfaction. The association between questionnaire outcomes and patient characteristics was investigated. Results Fifty participants were included; they used an average of 9 (+/- SD 2.7) medicines. For most participants (82%), the necessity of using medicines outweighed their concerns. Participants could name 35% of their medicines and 43% of the indications. Overall, 76% were satisfied with the effect of their medicines, but 94% would be willing to stop their medication if advised by their doctor. Maintaining independence (46%) and reducing pain (31%) were the most important health outcome priorities reported by the patients; staying alive had the lowest priority (51%). Participants with higher levels of educational attainment had better knowledge and had more concerns about harmful effects. Conclusions Patients are open to deprescribing but would probably not initiate the conversation themselves because they are generally very satisfied with their medicines. Knowledge about their medicines and their indications is poor. If doctors initiate deprescribing, patients are probably willing to follow their advice. Patients’ life priorities should be discussed in deprescribing conversations.

Background In older patients with end-stage kidney disease (ESKD), the choice between kidney transplantation (KT) and dialysis may be more complex than in younger patients because of a higher prevalence of comorbidities and frailty. This study aims to provide greater insight into the current decision-making process by exploring the expectations, experiences and health outcome priorities of all stakeholders. Methods We performed semi-structured interviews with patients ≥65 years with ESKD (eGFR Results We performed 36 interviews (patients n = 18, relatives n = 5, healthcare professionals n = 13). Thematic analysis revealed five themes. Older patients’ health outcome priorities were mostly related to quality of life (QOL). Individual older patients showed marked differences in the preferred level of engagement during the decision-making process (varying from ‘wants to be in the lead’ to ‘follows the nephrologist’) and in informational needs (varying from evidence-based to experience-based). On the contrary, healthcare professionals were quite unanimous on all aspects. They focused on determining eligibility for KT as start of the decision-making process, on clear and extensive information provision and on classical, medical outcomes. Conclusions The decision-making process could benefit from early identification of older patients’ values, needs and health outcome priorities, in parallel with assessment of KT eligibility and before discussing the treatment options, and the explicit use of this information in further steps of the decision-making process.

Background:Psychotropic drugs are frequently prescribed to people with dementia in nursing homes although severe adverse events and side effects are common. Less is known about the prevalence and types of psychotropic drug prescription in primary care for people with dementia.Objective:This study examined the prevalence of psychotropic drug prescriptions in primary care among persons with dementia from the year of diagnosis onwards.Methods:A longitudinal observational study using electronic health record (EHR) data was conducted. People with dementia were selected from EHR data of 451 general practices in the Netherlands. Age and gender-adjusted psychotropic drug prescription rates were calculated per 1000 person-years from the year the dementia diagnosis was first recorded in general practice up to 8 years after diagnosis.Results:Data of 15,687 patients were analyzed. The prescription rate of psychotropic drugs (not including antidementia drugs) was 420 per 1000 person-years (95% CI 409; 431) in the first year after the recorded dementia diagnosis, which increased to 801 per 1000 person-years (95% CI 649; 989) in the eighth year. The most frequently prescribed drugs were antidepressants, antipsychotics, and antidementia drugs, followed by anxiolytics, hypnotics, and antiepileptics.Conclusions:After a dementia diagnosis is recorded in general practice, the prevalence of psychotropic drug prescriptions is substantial and increases steadily during the disease trajectory of persons with dementia. Although the (in)appropriateness of prescribing was not assessed, these insights may stimulate primary care clinicians to (re)consider their prescription policy of psychotropics for people with dementia more carefully.

Background Frailty and adverse drug effects are linked in the fact that polypharmacy is correlated with the severity of frailty; however, a causal relation has not been proven in older people with clinically manifest frailty. Methods A literature search was performed in Medline to detect prospective randomized controlled trials (RCTs) testing the effects of pharmacological interventions or medication optimization in older frail adults on comprehensive frailty scores or partial aspects of frailty that were published from January 1998 to October 2019. Results Twenty-five studies were identified, 4 on comprehensive frailty scores and 21 on aspects of frailty. Two trials on comprehensive frailty scores showed positive results on frailty although the contribution of medication review in a multidimensional approach was unclear. In the studies on aspects related to frailty, ten individual drug interventions showed improvement in physical performance, muscle strength or body composition utilizing alfacalcidol, teriparatide, piroxicam, testosterone, recombinant human chorionic gonadotropin, or capromorelin. There were no studies examining negative effects of drugs on frailty. Conclusion So far, data on a causal relationship between drugs and frailty are inconclusive or related to single-drug interventions on partial aspects of frailty. There is a clear need for RCTs on this topic that should be based on a comprehensive, internationally consistent and thus reproducible concept of frailty assessment.

Objectives To investigate the prevalence of potentially inappropriate prescribing (PIP) according to the revised STOPP/START criteria in older patients with falls and syncope. Study design We included consecutive patients with falls and syncope aged ≥65 years at the day clinic of the Northwest Clinics, the Netherlands, from 2011 to 2016. All medication use before and after the visit was retrospectively investigated using the revised STOPP/START criteria. Main outcome measures The prevalence/occurrence of PIP before the visit, persistent PIP after the visit, and unaddressed persistent PIP not explained in the patient’s chart. Results PIP was present in 98 % of 374 patients (mean age 80 (SD ± 7) years; 69 % females). 1564 PIP occurrences were identified. 1015 occurrences persisted (in 91 % of patients). 690 occurrences (in 80 % of patients) were not explained in the patient’s chart. The most frequent unaddressed persistent forms of PIP were prescriptions of vasodilator drugs for patients with orthostatic hypotension (16 %), and benzodiazepines for >4 weeks (10 %) or in fall patients (8 %), and omission of vitamin D (28 %), antihypertensive drugs (24 %), and antidepressants (17 %). 54 % of all medication changes were initiated for reasons beyond the scope of the STOPP/START criteria. Conclusions Almost every patient in our study population suffered from PIP. In 80 %, PIP continued after the clinical visit, without an explanation in the patient’s chart. The most frequent PIP concerned medication that increased the risk of falls or syncope, specifically vasodilator drugs and benzodiazepines. Physicians should be aware of PIP in older patients with falls and syncope. Further studies should investigate whether a structured medication review may improve clinical outcomes.

BackgroundPersonal continuity of care is a core value of general practice. It is increasingly threatened by societal and healthcare changes.AimTo investigate the association between personal continuity and both practice and patient characteristics; and to incorporate GPs’ views to enrich and validate the quantitative findings.Design and settingA mixed-methods study based on observational, routinely collected healthcare data from 269 478 patients from 48 Dutch general practices (2013–2018) and interviews with selected GPs.MethodFirst, four different personal continuity outcome measures were calculated relating to eight practice and 12 patient characteristics using multilevel linear regression analyses. Second, a thematic analysis was performed of semi-structured interviews with 10 GPs to include their views on factors contributing to personal (dis) continuity. These GPs worked at the 10 practices with the largest difference between calculated and model-estimated personal continuity.ResultsBoth a larger number of usual GPs working in a practice and a larger percentage of patient contacts with locum GPs were dose-dependently associated with lower personal continuity (highest versus lowest quartile −0.094 and −0.092, respectively,PPConclusionPersonal continuity is associated with practice and patient characteristics. The dose-dependent associations suggest a causal relationship and, complemented by GPs’ views, may provide practical targets to improve personal continuity directly.

Background Cognitive decline is common in older people. Numerous studies point to the detrimental impact of polypharmacy and inappropriate medication on older people’s cognitive function. Here we aim to systematically review evidence on the impact of medication optimisation and drug interventions on cognitive function in older adults. Methods A systematic review was performed using MEDLINE and Web of Science on May 2021. Only randomised controlled trials (RCTs) addressing the impact of medication optimisation or pharmacological interventions on quantitative measures of cognitive function in older adults (aged > 65 years) were included. Single-drug interventions (e.g., on drugs for dementia) were excluded. The quality of the studies was assessed by using the Jadad score. Results Thirteen studies met the inclusion criteria. In five studies a positive impact of the intervention on metric measures of cognitive function was observed. Only one study showed a significant improvement of cognitive function by medication optimisation. The remaining four positive studies tested methylphenidate, selective oestrogen receptor modulators, folic acid and antipsychotics. The mean Jadad score was low (2.7). Conclusion This systematic review identified a small number of heterogenous RCTs investigating the impact of medication optimisation or pharmacological interventions on cognitive function. Five trials showed a positive impact on at least one aspect of cognitive function, with comprehensive medication optimisation not being more successful than focused drug interventions. More prospective trials are needed to specifically assess ways of limiting the negative impact of certain medication in particular and polypharmacy in general on cognitive function in older patients. publishedVersion

Objective: The objective of this systematic review was to provide a critical appraisal of the evidence related to the safety of clozapine for schizophrenia during pregnancy and lactation. Data Sources: PubMed/MEDLINE, Embase, and the Cochrane Library were searched from inception through December 2020. Reference lists of included studies were hand-searched. The International Clinical Trials Registry Platform and ClinicalTrials.gov were searched for unpublished trials, and PROSPERO was searched for unpublished reviews. The current marketing authorization holder of the originator brands Clozaril and Leponex was also contacted for pharmacovigilance data. Study Selection: Original reports published in English, German, French, or Dutch containing clinical and preclinical data were included if they provided data on maternal, fetal, and neonatal outcomes after clozapine exposure during pregnancy or lactation. Data Extraction: Two reviewers independently extracted relevant data. Results: A total of 860 records were identified, and the full texts of 117 articles were reviewed. Forty-two studies met the inclusion criteria. Data on perinatal clozapine exposure are of limited quality and quantity. Although clozapine demonstrates partial placental passage, data thus far do not support that clozapine is teratogenic; that it increases the risk of stillbirth, abortion, or fetal disorders; or that it increases the risk of delivery complications or premature birth. Information about clozapine exposure through breast milk is scarce, but based on its chemical properties, it is likely that clozapine enters the breast milk of nursing mothers taking clozapine. Conclusions: When weighing the risks and benefits of clozapine continuation during pregnancy and lactation versus switching to another antipsychotic, one should include severity of illness and treatment history but also be aware of the limitations of the available safety data regarding perinatal clozapine use, including the fact that there are few studies.

Correction to: European Journal of Clinical Pharmacology (2021) 77:1–12 https://doi.org/10.1007/s00228-020–02951-8 \ud \ud The article Current evidence on the impact of medication optimization or pharmacological interventions on frailty or aspects of frailty: a systematic review of randomized controlled trials, written by Farhad Pazan, Mirko Petrovic, Antonio Cherubini, Graziano Onder, Alfonso J. Cruz-Jentoft, Michael Denkinger, Tischa J. M. van der Cammen, Jennifer M. Stevenson, Kinda Ibrahim, Chakravarthi Rajkumar, Marit Stordal Bakken, Jean-Pierre Baeyens, Peter Crome, Thomas Frühwald, Paul Gallaghar, Adalsteinn Guðmundsson, Wilma Knol, Denis O’Mahony, Alberto Pilotto, Elina Rönnemaa, José Antonio Serra-Rexach, George Soulis, Rob J. van Marum, Gijsbertus Ziere, Alpana Mair, Heinrich Burkhardt, Agnieszka Neumann-Podczaska, Katarzyna Wieczorowska- Tobis, Marilia Andreia Fernandes, Heidi Gruner, Dhayana Dallmeier, Jean-Baptiste Beuscart, Nathalie van der Velde and Martin Wehling, was originally published electronically on the publisher’s internet portal on 07 August 2020 without open access. With the author(s)’ decision to opt for Open Choice the copyright of the article changed on 14 May 2021 to © The Author(s) 2021 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4.0. \ud The Original article has been corrected.

The antipsychotic drug clozapine is associated with weight gain. The proposed mechanisms include blocking of serotonin (5-HT2a/2c ), dopamine (D2 ) and histamine (H1 ) receptors. Clozapine is metabolized by cytochrome P450 1A2 (CYP1A2) to norclozapine, a metabolite with more 5-HT2c -receptor and less H1 blocking capacity. We hypothesized that norclozapine serum levels correlate with body mass index (BMI), waist circumference and other parameters of the metabolic syndrome. We performed a retrospective cross-sectional study in 39 patients (female n = 8 (20.5%), smokers n = 18 (46.2%), average age 45.8 ± 9.9 years) of a clozapine outpatient clinic in the Netherlands between 1 January 2017 and 1 July 2020. Norclozapine concentrations correlated with waist circumference (r = 0.354, P = .03) and hemoglobin A1c (HbA1c) (r = 0.34, P = .03). In smokers (smoking induces CYP1A2), norclozapine concentrations correlated with waist circumference (r = 0.723, P = .001), HbA1c (r = 0.49, P = .04) and BMI (r = 0.63, P = .004). Elucidating the relationship between norclozapine and adverse effects of clozapine use offers perspectives for interventions and treatment options.

PURPOSE/BACKGROUND: The duration of untreated depression is a predictor for poor future prognosis, making rapid dose finding essential. Genetic variation of the CYP2D6 isoenzyme can influence the optimal dosage needed for individual patients. The aim of this study was to determine the effectiveness of CYP2D6 pharmacogenetic screening to accelerate drug dosing in older patients with depression initiating nortriptyline or venlafaxine.METHODS/PROCEDURES: In this randomized controlled trial, patients were randomly allocated to one of the study arms. In the intervention arm (DG-I), the specific genotype accompanied by a standardized dosing recommendation based on the patients' genotype and the prescribed drug was directly communicated to the physician of the participant. In both the deviating genotype control arm (DG-C) and the nonrandomized control arm, the physician of the participants was not informed about the genotype and the associated dosing advise. The primary outcome was the time needed to reach adequate drug levels: (1) blood levels within the therapeutic range and (2) no dose adjustments within the previous 3 weeks.FINDINGS/RESULTS: No significant difference was observed in mean time to reach adequate dose or time to adequate dose between DG-I and DG-C. Compared with the nonrandomized control arm group, adequate drug levels were reached significantly faster in the DG-I group (log-rank test; P = 0.004), and there was a similar nonsignificant trend for the DG-C group (log-rank test; P = 0.087).IMPLICATIONS/CONCLUSIONS: The results of this study do not support pharmacogenetic CYP2D6 screening to accelerate dose adjustment for nortriptyline and venlafaxine in older patients with depression.

De module Minderen en stoppen van medicatie, een nieuw onderdeel van de multidisciplinaire richtlijn (MDR) Polyfarmacie bij ouderen, is per 1 december 2020 beschikbaar. Ook zijn de STOPP-START-criteria aangepast.

Objective To prevent osteoporotic fractures in nursing home residents a combination of bisphosphonates, calcium and vitamin D is recommended. This study assessed the prevalence of pharmacological osteoporosis prevention in nursing home residents from eight countries, and assessed its association with patient characteristics. Design Cross-sectional analyses of the SHELTER study data. We assessed the overall prevalence of osteoporosis medication (OM) use (vitamin D, calcium and bisphosphonates) in residents stratified for falls and fractures over last 30 days, health instability with high mortality risk, cognitive impairment, and dependence in walking. Setting and Participants Nursing home residents in the Czech Republic, England, Finland, France, Germany, Italy, The Netherlands and Israel. Results Of 3832 eligible residents, vitamin D, calcium and bisphosphonates were used by 16.2%, 10.4%, and 4.5% respectively. All 3 classes of OM together were used by 1.5% of all residents. Of residents with a recent fracture, 9.5% used a bisphosphonate (2.7% all 3 OMs). In patients with recent falls, 20.8% used vitamin D and 15.3% calcium. In residents with severe cognitive impairment, 15.5% used vitamin D and 9.3% used calcium. Of the bisphosphonate users, 33.7% also used both vitamin D and calcium, 25.8% used only calcium in addition and 17.4% only vitamin D in addition. The use of any OM varied widely across countries, from 66.8% in Finland to 3.0% in Israel. Conclusions and Implications We found substantial pharmacological under-treatment of prevention of osteoporosis in residents with recent falls, fractures and dependence in walking. Only two-thirds of bisphosphonate users also took a vitamin D–calcium combination, despite guideline recommendations. On the other hand, possible over-treatment was found in residents with high mortality risk in whom preventive pharmacotherapy might not have still been appropriate. The prevalence of pharmacological prevention of osteoporosis differed substantially between countries. Efforts are needed to improve pharmacotherapy in residents.

De module Medicatiebeoordeling uit de Multidisciplinaire richtlijn Polyfarmacie bij ouderen is herzien. De primaire doelgroep is beperkt tot patienten van 75 jaar of ouder die tien of meer geneesmiddelen gebruiken en/of kwetsbaar zijn. Voor andere groepen zijn ook minder uitgebreide evaluaties beschikbaar. De nieuwe module is praktisch en beperkt de werklast voor huisarts en apotheker.

Introduction: In nursing home (NH) residents with a very short life expectancy, the benefits of preventive cardiovascular medication maintenance are questionable. Objective: To assess the prevalence of 4 classes of preventive cardiovascular medication (PCM) in NH residents, and to explore differences of prevalence across length of stay, mortality risk, cognitive impairment, functional disability, and across countries. Methods: A 12-month prospective cohort study was conducted in 57 NHs in 8 countries (Czech Republic, England, Finland, France, Germany, Italy, The Netherlands, and Israel). We assessed the prevalence at first measurement of 4 classes of PCM: oral anticoagulants (OAC), platelet aggregation inhibitor (PAI), antihypertensive (AHT), and lipid-modifying agent (LMA), in older (60+ years) residents with valid medication assessments. The PCM prevalence was compared across the length of stay (short 12 months), health instability as defined by Changes in Health, End-Stage Disease, Signs, and Symptoms Scale (CHESS) > 3, cognitive impairment by Cognitive Performance Scale (CPS) > 2, and functional disability was measured using the Activities of Daily Living Hierarchy Scale (ADLH) ≥5. Results: Of the 3759 eligible residents, 2175 (57.9%) used at least 1 PCM. The prevalence of the 4 groups of PCM: OAC, PAI, AHT and LMA were 5.6%, 34.9%, 35.7%, and 10.4%, respectively. PCM use was lower in long-stay residents versus mid-stay: 56.0% vs. 62.7%, in cognitively impaired residents (47.1% vs. 67%), in residents with a high mortality risk (47.4% vs. 58.6%), and in residents with a high ADLH score (48.6% vs 64.0%). Conclusion: Although the prevalence of PCM use was lower in long-stay, cognitively impaired residents, persons with a high mortality risk, and residents with more functional disabilities, there seems to be room for deprescribing.

The antidepressant nortriptyline is metabolized by cytochrome P450 2D6 (CYP2D6) to the less active and more cardiotoxic drug metabolite, 10-hydroxynortriptyline. High serum levels of this metabolite (>200 μg/L) may lead to withdrawal of nortriptyline therapy. Adding CYP2D6 inhibitors reduce the metabolic activity of CYP2D6 (phenoconversion) and so decrease the forming of hydroxynortriptyline. In this study, 5 mg paroxetine is administered to patients with high hydroxynortriptyline concentrations (>200 μg/L). The shift in number of patients to therapeutic nortriptyline (50-150 μg/L) and safe hydroxynortriptyline (

Background The rapid digitalization of medical practice has attracted growing interest in developing software applications for clinical guidelines and explicit screening tools to detect potentially inappropriate prescribing, such as STOPP/START criteria. The aim of the current study was to develop and provide logically unambiguous algorithms of STOPP/START criteria version 2, encoded with international disease and medication classification codes, to facilitate the development of software applications for multiple purposes. Methods A four round multidisciplinary consensus and validation procedure was conducted to develop implementable coded algorithms for software applications of STOPP/START criteria version 2, based on ICD, ICPC, LOINC and ATC classification databases. Results Consensus was reached for all 34 START criteria and 76 out of 80 STOPP criteria. The resulting 110 algorithms, modeled as inference rules in decision tables, are provided as supplementary data. Conclusion This is the first study providing implementable algorithms for software applications based on STOPP/START version 2, validated in a computer decision support system. These algorithms could serve as a template for applying STOPP/START criteria version 2 to any software application, allowing for adaptations of the included ICD, ICPC and ATC codes and changing the cut-off levels for laboratory measurements to match local guidelines or clinical expertise.

Although many older patients use analgesics from time to time, little is known about the safety and efficacy of these medicines in older people. The balance between effectiveness and side effects may be totally different from what is expected. Physiological and pathophysiological changes can cause the pharmacokinetics and pharmacodynamics of medicines to change. Drug-drug interactions can enhance or decrease the effects of medicines. In frail older people with multimorbidity and polypharmacy in particular, these changes may lead to a higher risk of side effects and a decline in the analgesic effect. The vulnerability of many older people means that even when pain is adequately controlled, concomitant side effects of medicines can have a big negative impact on their general functioning. Pharmacological pain management in older people requires specific competences and knowledge. In this article we present 10 tips for pain management in older people from a pharmacological perspective.

Purpose: To investigate: (1) the cross-sectional association between polypharmacy, hyperpolypharmacy and presence of prefrailty or frailty; (2) the risk of incident prefrailty or frailty in persons with polypharmacy, and vice versa. Methods: A systematic review and meta-analysis was performed according to PRISMA guidelines. We searched PubMed, Web of Science, and Embase from 01/01/1998 to 5/2/2018. Pooled estimates were obtained through random effect models and Mantel–Haenszel weighting. Homogeneity was assessed with the I 2 statistic and publication bias with Egger’s and Begg’s tests. Results: Thirty-seven studies were included. The pooled proportion of polypharmacy in persons with prefrailty and frailty was 47% (95% CI 33–61) and 59% (95% CI 42–76), respectively. Increased odds ratio of polypharmacy were seen for prefrail (pooled OR = 1.52; 95% CI 1.32–1.79) and frail persons (pooled OR = 2.62, 95% CI 1.81–3.79). Hyperpolypharmacy was also increased in prefrail (OR = 1.95; 95% CI 1.41–2.70) and frail (OR = 6.57; 95% CI 9.57–10.48) persons compared to robust persons. Only seven longitudinal studies reported data on the risk of either incident prefrailty or frailty in persons with baseline polypharmacy. A significant higher odds of developing prefrailty was found in robust persons with polypharmacy (pooled OR = 1.30; 95% CI 1.12–1.51). We found no papers investigating polypharmacy incidence in persons with prefrailty/frailty. Conclusions: Polypharmacy is common in prefrail and frail persons, and these individuals are also more likely to be on extreme drug regimens, i.e. hyperpolypharmacy, than robust older persons. More research is needed to investigate the causal relationship between polypharmacy and frailty syndromes, thereby identifying ways to jointly reduce drug burden and prefrailty/frailty in these individuals. Prospero registration number: CRD42018104756.

Purpose: Safety data on clozapine use during pregnancy are limited. The aim of this study was to determine disproportionality in case safety reports on adverse pregnancy outcomes between clozapine and other antipsychotics (OAP) used during pregnancy. Methods: We included all reports of suspected adverse drug reactions (ADRs) to antipsychotics registered in the World Health Organization global individual case safety report (ICSR) database (VigiBase) in children younger than 2 years and women aged 12-45 years. A case/non-case approach was used to evaluate the association between several pregnancy-related ADRs and clozapine exposure during pregnancy, using 2×2 contingency tables to investigate disproportionality and Standard MedDRA Queries to select cases. Clozapine exposure was defined as all ICSR-ADR combinations with clozapine as (one of) the suspected drug(s). Non-exposure was defined as all ICSR-ADR combinations with OAP as (one of) the suspected drug(s). Results: We identified 42 236 unique ICSR-ADR combinations related with clozapine exposure and 170 710 with OAP exposure. Of these, 494 and 4645 ICSR-ADR combinations involved adverse pregnancy outcomes related with clozapine exposure and OAP exposure respectively. Overall, no signal of disproportionate reporting associating clozapine with the studied adverse pregnancy outcomes was found compared with OAP exposure. Conclusion: Based on global pharmacovigilance data, we did not find any evidence that clozapine is less safe during pregnancy than OAP. Although this is not automatically equivalent to the relative safety of clozapine during pregnancy, these findings add to the convergence of proofs to allow final conclusions and decisions regarding the treatment of pregnant women with clozapine.

Background Treatment with antipsychotic drugs has been associated with glucose dysregulation in older outpatients, especially in the early stage of therapy. The underlying mechanism is, however, unclear. The aim of this study was to investigate changes in glucose levels during haloperidol use compared with the use of placebo among older hospitalized patients. Methods This substudy was part of a larger multicenter, randomized, double blind, placebo-controlled clinical trial among hospitalized patients aged 70 years and older who had an increased risk of in-hospital delirium. Patients who were admitted to the Jeroen Bosch Hospital in 's-Hertogenbosch between June 2014 and February 2015 were invited to participate in the study. Participating patients were randomized for treatment and given 1 mg of haloperidol or a placebo twice daily for a maximum of 7 consecutive days (14 doses). Exclusion criteria for this substudy were the use of corticosteroids and changes in diabetes medication. Random blood samples to determine glucose levels were collected before day 1 and on day 6 of the study. Student independent sample t test was used to determine differences in glucose changes between both groups. Results Twenty-nine patients were included (haloperidol, n = 14; placebo, n = 15). The mean glucose level for placebo users was 139.3 mg/dL (SD, 50.1) on day 1 and 140.8 mg/dL (SD, 45.7) on day 6, and the mean glucose level for haloperidol users was 139.9 mg/dL (SD, 71.0) on day 1 and 150.2 mg/dL (SD, 39.1) on day 6. The difference was not statistically significant (P = 0.685). Conclusions Short-term prophylactic use of haloperidol was not associated with changes in glucose levels in older hospitalized patients compared with those given a placebo in this small study.

Purpose/background Cessation of clozapine therapy and insufficient response may result in relapse of psychotic symptoms and in clinical admissions. However, discontinuation rates are high. Identifying patients at risk for unsuccessful clozapine use might enable clinicians to direct specific attention to them. Methods/procedures Routinely collected data from a large insurance company were used to develop a simple prediction model for unsuccessful clozapine treatment in psychiatric patients 1 year after clozapine was first dispensed by a community pharmacy in the Netherlands. Multivariate logistic regression analyses were performed with the Nagelkerke R statistic as a measure of the predictive value of the model. Findings/results A total of 937 patients were dispensed clozapine for the first time by their community pharmacy between January 1, 2011, and December 31, 2015 (index date). Of these, 741 patients had started their clozapine treatment in hospital before the index date (inpatient starters); the remaining 196 patients started clozapine as outpatients on the index date (outpatient starters). In 191 patients (20.4%), clozapine treatment was unsuccessful 1 year after the index date. Unsuccessful treatment was more common among outpatient starters than among inpatient starters (32.1% vs 17.3%). Using backward selection of the variables, a model consisting of 61 variables had the best predictive value overall (Nagelkerke R = 0.301), whereas a model consisting of 52 variables had the best predictive value in outpatient starters (Nagelkerke R = 0.676). Implications/conclusions The likelihood of unsuccessful clozapine treatment after 1 year was higher among patients who started clozapine as outpatients. Despite the use of a diversity of variables and different statistical approaches, it was not possible to make a simple prediction model for unsuccessful clozapine treatment using relatively easily accessible data.

Objective To determine whether advised changes as a result of structured medication reviews in psychogeriatric patients were implemented and if the implemented changes were maintained. Design Prospective cohort study. Setting Three nursing facilities in The Netherlands. Patients, participants Newly admitted psychogeriatric residents. Intervention After admission, a structured medication review was performed by a pharmacist and physician resulting in a treatment plan that was approved by the patient's legal representative and implemented. Main outcome measure(s) The percentage of advised changes approved (= approval rate) and the percentage of implemented medication changes still present 90 days after approval (= 90-day implementation rate). Results A total of 45 patients were included who used a total number of 333 drugs (mean ± standard deviation 7.4 ± 3.3 drugs). Changes were advised to 159 medications used by 42 patients. Of these changes, 150 were approved (approval rate 94.3%). Finally, 105 were implemented, and 89 were still implemented after 90 days (90-day implementation rate 84.8%). Overall, 59.7% of the advised changes concerned deprescribing (stopping or dose reduction). The proportion of advised changes implemented was similar for symptommodifying and risk-modifying drugs, namely, almost 85%. Overall, 55.3% of the recommended changes to deprescribe concerned 10 drug groups. Conclusion Medication could be successfully deprescribed from psychogeriatric patients after structured medication reviews performed by pharmacists and nursing facility physicians. More than 50% of the advised changes to deprescribe involved 10 drug groups, which raises the question whether the structured medication review can be performed more efficiently by focusing on the most common problems.

Background: because the few randomised placebo-controlled trials investigating the potential role for prophylactic haloperidol in delirium prevention have focused on specific surgical populations, we investigated its efficacy and safety in acutely hospitalised older patients.Methods: this multi-centre, double-blind, stratified, block randomised, placebo-controlled trial was conducted at six Dutch hospitals. Patients age ≥ 70 years, acutely admitted through the emergency department for general medicine or surgical specialties and at risk for delirium were randomised (n = 245) to haloperidol or placebo 1 mg orally twice-daily (maximum of 14 doses) on top of standard nonpharmacological prevention strategies. The primary outcome was delirium incidence. Other endpoints included delirium severity and duration, drug safety and clinical outcomes.Results: intention-to-treat analysis included 242 participants (calculated sample size n = 390, statistical power of current sample 59%) allocated to haloperidol (n = 118) or placebo (n = 124). In the haloperidol and placebo group, delirium incidence was 19.5 versus 14.5% (OR 1.43, 95% CI 0.72 to 2.78); median (IQR) delirium duration 4 (2, 5) versus 3 (1, 6) days (P = 0.366); maximum DRS-R-98 score 16 (9.8, 19.5) versus 10 (5.5, 22.5) (P = 0.549; 53.7% missing data); hospital LOS 7 (4, 10.3) versus 7 (5, 11.8) days (P = 0.343); 3-month mortality 9.9 versus 12.5% (OR 0.77, 95% CI 0.34 to 1.75), respectively. No treatment-limiting side effects were noted.Conclusions: prophylactic low-dose oral haloperidol did not reduce delirium incidence in acutely hospitalised older patients. Therefore, prophylactic use of haloperidol in this population is not recommended.

Introduction We compared the automated Elecsys and manual Innotest immunoassays for cerebrospinal fluid (CSF) Alzheimer's disease biomarkers in a multicenter diagnostic setting. Methods We collected CSF samples from 137 participants in eight local memory clinics. Amyloid β(1–42) (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) were centrally analyzed with Innotest and Elecsys assays. Concordances between methods were assessed. Results Biomarker results strongly correlated between assays with Spearman's ρ 0.94 for Aβ42, 0.98 for t-tau, and 0.98 for p-tau. Using Gaussian mixture modeling, cohort-specific cut-points were estimated at 1092 pg/mL for Aβ42, 235 pg/mL for t-tau, and 24 pg/mL for p-tau. We found an excellent concordance of biomarker abnormality between assays of 97% for Aβ42 and 96% for both t-tau and p-tau. Discussion The high concordances between Elecsys and Innotest in this nonacademic, multicenter cohort support the use of Elecsys for CSF Alzheimer's disease diagnostics and allow conversion of results between methods., Highlights • Method comparison of 137 CSF samples collected in eight nonacademic memory clinics. • Innotest and Elecsys strongly correlated: ρ = 0.94 Aβ42; 0.98 t-tau; 0.98 p-tau. • Concordances of biomarker abnormalities: 97% Aβ42; 96% t-tau and p-tau. • Concordance of NIA-AA–based Alzheimer's disease profile (Aβ42 decreased and p-tau increased): 89%. • Preanalytical protocol deviations did not show effects on biomarker correlations.

Treatment of Alzheimer disease (AD) with cholinesterase inhibitors (ChEIs) may increase the risk of urinary incontinence (UI). Objective: To assess whether ChEI use was associated with the risk of UI among older patients with AD. Methods: A crossover cohort study using the PHARMO Record Linkage System included 10years of data on drug dispensing histories for over two million Dutch residents. Included patients were aged 50 +, free of UI for the last 6months, received a first ChEI prescription during the study period, had at least 12months prior drug exposure history and one subsequent prescription of any drug. UI was defined as a first dispensing of a urinary spasmolytic or of incontinence products for at least 30days. Cox regression with time-varying covariates and multivariate adjustment allowed assessing whether UI incidence was associated with ChEI exposure. Results: Among 3154 patients there were 657 UI cases during a mean follow-up of 5.1years before a first ChEI dispensing, and 499 cases after ChEI initiation, during a mean follow-up of 2.0years. Among the 2700 participants free of UI one year before ChEI initiation, the adjusted hazard ratio (HR) for UI was 1.13 (95% CI: 0.97-1.32) when periods with ChEI use were compared to periods without ChEI use. Sensitivity analyses may suggest an increased risk in the 1st month after ChEI initiation (HR: 1.72, p=0.09) Conclusion: Worsening AD may increase incidence of UI, but no firm association between ChEI treatment and risk of UI could be shown from these data.

OBJECTIVE: In dialysis-dependent and severe chronic kidney disease (CKD) patients, cognitive impairment is found in 16-29%. In community-dwelling population without dementia mixed results have been observed. We investigated the relationship between renal function and cognition in patients from a memory clinic. METHODS: We performed a cross-sectional study of consecutive patients from a memory clinic between 2005 and 2009. Renal function was estimated with the Modification of Diet in Renal Diseases (MDRD) and Cockcroft-Gault (CG) formulas, and categorized into ordinal groups: reference ≥ 60 ml/min/1.73 m(2), mild CKD 45-59 ml/min/1.73 m(2) and moderate CKD

Polypharmacy and inappropriate prescribing are common among nursing home residents with dementia. In many cases, medication is not discontinued despite the very limited life expectancy of these individuals, the increased risk of side effects due to drug-drug and drug-disease interactions, and the questionable benefits of medication. A structured approach is essential to managing the medication of nursing home residents with dementia. To facilitate rational prescribing, the WHO six-step method should be used. But it is also important to perform periodical medication reviews in which the appropriateness of the total medication set is evaluated. These medication reviews should be performed in a systematic manner in close collaboration between patient/caregiver, physician, and pharmacist. At the end of life, it can be expected that pharmacotherapeutic goals gradually chance from largely preventive to more symptomatic therapy. In this chapter, the problems related to polypharmacy are described. Guidelines, based on the WHO six step, are given on how to make rational choices when prescribing for individuals with dementia and on how to perform a medication review. Lastly, attention is given to issues concerning the stopping or withdrawal of medication.

Background: the STOPP/START criteria are a promising framework to increase appropriate prescribing in the elderly in clinical practice. However, the current definitions of the STOPP/START criteria are rather non-specific, allowing undesirable variations in interpretation and thus application. The aim of this study was to design specifications of the STOPP/START criteria into international disease and medication codes to facilitate computerised extraction from medical records and databases. Methods: a three round consensus procedure with a multidisciplinary expert panel was organised to prepare, judge and agree on the design of the STOPP/START criteria specifications in corresponding international disease codes (ICD9 and ICPC) and medication codes (ATC). Results: after two rounds consensus was reached for 74% of the STOPP criteria and for 73% of the START criteria. After three rounds full consensus was reached resulting in a specification of 61 out of 62 STOPP criteria and 26 START criteria with their corresponding codes. One criterion could not be specified and for some criteria corresponding disease codes were lacking or imperfect. Conclusion: this study showed the necessity of a consensus procedure as even experts frequently differed on how to specify the STOPP/START criteria. This specification enables next steps such as prognostic validation of these criteria on adverse outcomes and studying the impact of improving appropriate prescribing in the elderly.

Aim of the study was to analyze temporal trends in prevalence of hyponatremia over four decades in different settings. A systematic review of the literature from 1966 to 2009 yielded prevalences of hyponatremia, with standard errors (SE) and pooled estimated means (PEM), calculated by year and setting (geriatric, ICU, other hospital wards, psychiatric hospitals, nursing homes, outpatients). 53 studies were included. Prevalence of hyponatremia was stable from 1976 to 2006, and higher on geriatric wards accept for ICU: e.g. PEM prevalence of mild hyponatremia (serum sodium

Background Two cholinesterase inhibitors (ChEIs), rivastigmine and galantamine, are used to treat Alzheimer disease in the Netherlands. Several adverse cardiac events have been reported for these medications. Objective We aimed to assess if the use of ChEIs increased the risk of cardiac events in the Netherlands. Methods A cohort crossover study of the PHARMO Record Linking System database included patients who initiated ChEIs at age 50 years or older, had at least 1 dispensing of a ChEI drug between 1998 and 2008, a 1-year history in PHARMO, and 1 subsequent dispensing of any medication. Two outcomes were assessed: a first hospitalization for syncope or atrioventricular block. Poisson and Cox regression were used to calculate incidence densities and hazard ratios for cardiac events during periods with ChEI use, compared with periods without ChEI use. Results During the complete observation period of 8.9 years (interquartile range 6.7 to 10.2) there were 132 first hospitalizations for atrioventricular block and 17 first hospitalizations for syncope among 3358 patients. The adjusted incidence densities were significantly increased during ChEI exposure for syncope and atrioventricular block, when compared with the background incidence densities in the roughly 5 years before the last year before ChEI initiation. However, when exposed periods were compared with the unexposed periods 1 year before ChEI initiation and times after exposure, the adjusted hazard ratios remained increased for syncope and atrioventricular block, but increases were not significant anymore. Conclusions Exposure to ChEIs might increase the risk of adverse cardiac events, but small numbers of cases limit conclusions about the risk in this population and research on larger study samples is needed.

The incidence of spondylodiscitis is highest among the elderly. Because of the ageing population the incidence of spondylodiscitis is rising. In this article, we illustrate dilemmas which may occur when treating older patients with spondylodiscitis by presenting two cases. The first patient is a 74-year-old man in whom there was uncertainty about the diagnosis on the basis of imaging results. The second patient is an 82-year-old man with dementia in whom longstanding intravenous treatment was too burdensome and treatment with oral antibiotics was started. The diagnosis of spondylodiscitis in elderly can be challenging because of frequent atypical presentation and comorbidity. So far, there is not much known about the prognosis of spondylodiscitis in the elderly, which make decisions about treatment difficult. The prognosis seems worse in elderly with multimorbidity. A comprehensive geriatric assessment can help to guide treatment decisions by estimating the chance of good functional recovery.

Objective: For general practitioners (GPs) dizziness is a challenging condition to deal with. Data on the management of dizziness in older patients are mostly lacking. Furthermore, it is unknown whether GPs attempt to decrease Fall Risk Increasing Drugs (FRIDs) use in the management of dizziness in older patients. The aim of this study is to gain more insight into GP’s management of dizziness in older patients, including FRID evaluation and adjustment. Design: Data were derived from electronic medical records, obtained over a 12-month period in 2013. Setting: Forty-six Dutch general practices. Patients: The study sample comprised of 2812 older dizzy patients of 65 years and over. Patients were identified using International Classification of Primary Care codes and free text. Main outcome measures: Usual care was categorized into wait-and-see strategy (no treatment initiated); education and advice; additional testing; medication adjustment; and referral. Results: Frequently applied treatments included a wait-and-see strategy (28.4%) and education and advice (28.0%). Additional testing was performed in 26.8%; 19.0% of the patients were referred. Of the patients 87.2% had at least one FRID prescription. During the observation period, GPs adjusted the use of one or more FRIDs for 11.7% of the patients. Conclusion: This study revealed a wide variety in management strategies for dizziness in older adults. The referral rate for dizziness was high compared to prior research. Although many older dizzy patients use at least one FRID, FRID evaluation and adjustment is scarce. We expect that more FRID adjustments may reduce dizziness and dizziness-related impairment. Key Points It is important to know how general practitioners manage dizziness in older patients in order to assess potential cues for improvement. This study revealed a wide variety in management strategies for dizziness in older patients. There was a scarcity in Fall Risk Increasing Drug (FRID) evaluation and adjustment. The referral rate for dizziness was high compared with previous research.

Objective To examine the association between antipsychotic use and the risk of acute coronary syndrome (ACS) in elderly de novo users of antipsychotics. Design A community-based nested case-control study. Setting Pharmacy dispensing records from community pharmacies in The Netherlands were linked to hospital discharge records of 950 000 community-dwelling residents from 1998 to 2008. Patients Cases were 2803 patients aged 60 years or older, with a first hospital admission for ACS identified within a cohort of 26 157 elderly persons with at least one antipsychotic prescription (de novo users). For each case, four controls with no hospitalisation for ACS (n=11 024) were randomly selected from the same cohort, matched by age, gender and duration of registration in the database. Main outcome measures Relative risks, expressed as ORs, for ACS associated with antipsychotic drug use adjusted for comorbidity. Results Current exposure to antipsychotics was associated with a decreased risk of hospitalisation for ACS compared with past users (adjusted OR 0.5, 95% CI 0.5 to 0.6). Cumulative use up to 100 Defined Daily Doses was also associated with a decreased risk of hospitalisation (OR 0.7, CI 0.6 to 0.8). No differences in risk were found between typical and atypical antipsychotics, current dosage or different degrees of serotonergic, histaminergic or adrenergic affinity of the antipsychotic. Conclusions A decreased risk of hospitalisation for ACS in elderly patients currently using antipsychotics was found. Further research is needed to confirm our results and to determine whether there is a cardioprotective effect or a high non-referral rate in elderly antipsychotic users with ACS.

Background Earlier studies have shown poor documentation of the reasons for medication discontinuation during hospitalization. Communication of reasons for discontinuation, e.g. adverse drug reactions (ADRs), to general practitioners and pharmacists was also found to be insufficient, leading to a rate of represcription after an ADR of 27 % during the first 6 months after discharge. Objective The aim of this study was to develop and implement a user-friendly electronic clinical decision support system to document reasons for medication discontinuation in hospitalized geriatric patients and to flag potentially undesirable represcriptions. Methods The electronic clinical decision support module was developed using the Gaston framework. Pop-up windows force physicians to document reasons for medication discontinuation, and the system alerts physicians to the represcription of drugs withdrawn because of an ADR. We interviewed users regarding the acceptability of the system. Results On a 20-bed geriatric ward, the electronic system documented 2,228 medication discontinuations and the reasons for them over 11.4 months and alerted physicians to represcription of drugs associated with an ADR 20 times. The system was considered to be user-friendly. Conclusions This clinical decision support system fulfilled its aims of documenting the reasons for medication discontinuation and alerting physicians to potentially undesirable represcription of previously withdrawn drugs. It was found to be user-friendly

Background: Elderly patients with multiple morbidities and polypharmacy are at an increased risk of adverse drug events (ADEs). Appropriate prescribing, preserving the balance between drug effectiveness and safety, and treatment adherence may prevent these ADEs. In this study, we investigated which drug properties, such as effectiveness, safety, clinical experience and convenience, are relevant to the choice of medicine most appropriate for frail elderly patients. Objectives: The primary aim of this study was to develop a set of criteria to assist in the selection of the most appropriate drug within a drug class for the treatment of frail elderly patients. A secondary goal was to test the usefulness of the set of criteria in the prescription of antipsychotics for delirium and behavioural and psychological symptoms of dementia (BPSD). Methods: Thirty-one criteria potentially relevant to the choice of appropriate drugs for frail elderly patients were selected on the basis of a literature search in MEDLINE (1966–2008), EMBASE (1947–2008) and the Cochrane Library (1993–2008). This list was reviewed by 46 experts (24 physicians, 22 pharmacists), who scored each item for relevance in clinical practice on a scale from 1 to 10 (where 1 is not important and 10 is very important). By consensus, the authors selected the most relevant criteria for the final set of criteria. The usefulness of the final set of criteria was assessed with regard to the prescription of antipsychotics for delirium and BPSD. Results: The final set of 23 items consisted of 3 items on effectiveness, 14 on safety, including pharmacokinetic and pharmacodynamic criteria, 3 on clinical experience and 3 on convenience. Assessment using these criteria of the appropriateness of antipsychotics prescribed for delirium and BPSD revealed that certain drugs should be prescribed with caution to patients with Parkinson’s disease and Lewy body dementia. Conclusions: The criteria identified in this study, selected on the basis of a literature review and clinical expert opinion, represent a promising approach for determining the appropriateness of a drug for use in frail elderly individuals relative to alternative drugs for the same indication or from the same class.