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Aims Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are antidiabetic agents that can have direct cardiac effects by impacting on cardiac ion transport mechanisms that control cardiac electrophysiology. We studied the association between SGLT-2i use and all-cause mortality and the risk of sudden cardiac arrest (SCA) in patients with type 2 diabetes. Methods Using data from the UK Clinical Practice Research Datalink, a cohort study among patients initiating a new antidiabetic drug class on or after January 2013 through September 2020 was conducted. A Cox regression with time-dependent covariates was performed to estimate the hazard ratios (HRs) of SCA and all-cause mortality comparing SGLT-2is with other second- to third-line antidiabetic drugs. Stratified analyses were performed according to sex, diabetes duration ( Results A total of 152 591 patients were included. Use of SGLT-2i was associated with a reduced HR of SCA when compared with other second- to third-line antidiabetic drugs after adjustment for common SCA risk factors, although this association marginally failed to reach statistical significance [HR: 0.62, 95% confidence interval (95% CI): 0.38–1.01]. The HR of all-cause mortality associated with SGLT-2i use when compared with other second- to third-line antidiabetics was 0.43 (95% CI: 0.39–0.48) and did not vary by sex, diabetes duration, or the presence of cardiovascular disease. SGLT-2i use remained associated with lower all-cause mortality in patients without concomitant insulin use (HR: 0.56, 95% CI: 0.50–0.63). Conclusion SGLT-2i use was associated with reduced all-cause mortality in patients with type 2 diabetes. The association between use of SGLT-2i and reduced risk of SCA was not statistically significant.

Background The Dutch Institute for Clinical Auditing (DICA) Medicines Program was set up in September 2018 to evaluate expensive medicine use in daily practice in terms of real-world effectiveness using only existing data sources. Objective The aim of this study is to describe the potential of the addition of declaration data to quality registries to provide participating centers with benchmark information about the use of medicines and outcomes among patients. Methods A total of 3 national population-based registries were linked to clinical and financial data from the hospital pharmacy, the Dutch diagnosis treatment combinations information system including in-hospital activities, and survival data from health care insurers. The first results of the real-world data (RWD) linkage are presented using descriptive statistics to assess patient, tumor, and treatment characteristics. Time-to-next-treatment (TTNT) and overall survival (OS) were estimated using the Kaplan-Meier method. Results A total of 21 Dutch hospitals participated in the DICA Medicines Program, which included 7412 patients with colorectal cancer, 1981 patients with metastasized colon cancer, 3860 patients with lung cancer, 1253 patients with metastasized breast cancer, and 7564 patients with rheumatic disease. The data were used for hospital benchmarking to gain insights into medication use in specific patient populations, treatment information, clinical outcomes, and costs. Detailed treatment information (duration and treatment steps) led to insights into differences between hospitals in daily clinical practices. Furthermore, exploratory analyses on clinical outcomes (TTNT and OS) were possible. Conclusions The DICA Medicines Program shows that it is possible to gather and link RWD about medicines to 4 disease-specific population-based registries. Since these RWD became available with minimal registration burden and effort for hospitals, this method can be explored in other population-based registries to evaluate real-world efficacy.

Aim Activated blood platelet products facilitate myocardial intracellular Ca2+ overload, thereby provoking afterdepolarizations and increasing susceptibility of ischemic myocardium to ventricular fibrillation (VF). These effects are counteracted in vitro by acetylsalicylic acid (ASA), but no prior study investigated whether ASA is associated with decreased out-of-hospital cardiac arrest (OHCA) risk on a population level. Therefore, we studied whether ASA and other antiplatelet drugs (carbasalate calcium, clopidogrel) are associated with decreased risk of OHCA. Methods We conducted a population-based case-control study among individuals (772 OHCA-cases with documented VT/VF, 2444 non-OHCA-controls) who had used antiplatelet drugs in the year before index-date (OHCA-date), and studied the association between current antiplatelet drug use and OHCA-risk with multivariable logistic regression analysis. Results ASA use was associated with reduced OHCA-risk (adjusted odds ratio (ORadj) 0.6 [0.5–0.8]), and more so in women (ORadj 0.3 [0.2–0.6]) than in men (ORadj 0.7 [0.5–0.95], Pinteraction 0.021). Carbasalate calcium was associated with decreased OHCA-risk in women (ORadj 0.5 [0.3–0.9]), but not in men (ORadj 1.3 [0.96–1.7], Pinteraction 0.005). Clopidogrel was not associated with reduction in OHCA-risk. Risk reduction associated with ASA in patients with OHCA was similar in the presence of acute myocardial infarction (AMI) (ORadj 0.6 [0.4–0.9]) and in the absence of AMI (ORadj 0.7 [0.4–1.2]). Conclusion ASA use was associated with reduced OHCA-risk in both sexes, and more so in women, while carbasalate calcium only protected women. Clopidogrel was not associated with reduced OHCA-risk.

Purpose To compare the effectiveness and safety of a drug in daily practice with the outcomes of a target non‐inferiority trial by rigorously mimickingin an observational study the trial's design features. Methods This cohort study was conducted using the British Clinical Practice Research Datalink (CPRD) to emulate the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial. Patients with atrial fibrillation who were newly prescribed (>=12 months of no use) either rivaroxaban or warfarinfrom October 2008 to December 2017 were included. Non‐inferiority of rivaroxaban to warfarin in the prevention of stroke or systemic embolism was assessed in different analysis populations (intention‐to‐treat [ITT], per‐protocol [PP], and as‐treated populations) using a hazardratio (HR) of 1.46 as the non‐inferiority margin. Major bleeding (safety outcome) was also assessed and compared to that of the target trial. All outcomes were analyzed using Cox‐proportional hazard analyses. Results We included 25,473 incident users of rivaroxaban (n=4,008) or warfarin(n=21,465). Similar to the trial, non‐inferiority in the primary out come was demonstrated in all three analysis populations: HR=1.04 (95%CI 0.84 to 1.30) (ITT), HR=0.98 (95%CI 0.70 to 1.38) (PP), and HR=1.11 (95%CI 0.86 to 1.42) (as‐treated). Risk of major bleeding was also similar to the target trial. Conclusion The results of this study provide supportive evidence to the effectiveness of rivaroxaban and adds knowledge on the usefulness of emulating a non‐inferiority trial to assess drug effectiveness.

BACKGROUND: Recent results of patients with advanced melanoma treated with first-line BRAF-MEK inhibitors in clinical trials showed 5-year survival in one-third of patients with a median overall survival (OS) of more than 2 years. This study aimed to investigate these patients' real-world survival and identify the characteristics of long-term survivors.PATIENTS AND METHODS: The study population consisted of patients with advanced cutaneous melanoma with a BRAF-V600 mutated tumor who were treated with first-line BRAF-MEK inhibitors between 2013 and 2017. Long-term survival was defined as a minimum OS of 2 years from start therapy.RESULTS: The median progression-free survival (mPFS) and median OS (mOS) of real-world patients (n = 435) were respectively 8.0 (95% CI, 6.8-9.4) and 11.7 (95% CI, 10.3-13.5) months. Two-year survival was reached by 28% of the patients, 22% reached 3-year survival and 19% reached 4-year survival. Real-world patients often had brain metastases (41%), stage IV M1c disease (87%), ECOG PS ≥2 (21%), ≥3 organ sites (62%) and elevated LDH of ≥250 U/I (49%). Trial-eligible real-world patients had an mOS of 17.3 months. Patients surviving more than 2 years (n = 116) more often had an ECOG PS ≤1 (83%), normal LDH (60%), no brain metastases (60%), no liver metastases (63%) and CONCLUSION: Long-term survival of real-world patients treated with first-line BRAF-MEK inhibitors is significantly lower than that of trial patients, which is probably explained by poorer baseline characteristics of patients treated in daily practice. Long-term survivors generally had more favorable characteristics with regard to age, LDH level and metastatic sites, compared to patients not reaching long-term survival.

Decentralized clinical trials (DCTs) have the potential to improve accessibility, diversity, and retention in clinical trials by moving trial activities to participants' homes and local surroundings. In this study, we conducted semi-structured interviews with 20 European regulators to identify regulatory challenges and opportunities for the implementation of DCTs in the European Union. The key opportunities for DCTs that were recognized by regulators include a reduced participation burden, which could facilitate the participation of underserved patients. In addition, regulators indicated that data collected in DCTs are expected to be more representative of the real world. Key challenges recognized by regulators for DCTs include concerns regarding investigator oversight and participants' safety when physical examinations and face-to-face contact are limited. To facilitate future learning, hybrid clinical trials with both on-site and decentralized elements are proposed by the respondents.

BackgroundIt is unknown whether patients undergoing primary percutaneous coronary intervention (PCI) benefit from genotype-guided selection of oral P2Y(12) inhibitors.MethodsWe conducted a randomized, open-label, assessor-blinded trial in which patients undergoing primary PCI with stent implantation were assigned in a 1:1 ratio to receive either a P2Y(12) inhibitor on the basis of early CYP2C19 genetic testing (genotype-guided group) or standard treatment with either ticagrelor or prasugrel (standard-treatment group) for 12 months. In the genotype-guided group, carriers of CYP2C19*2 or CYP2C19*3 loss-of-function alleles received ticagrelor or prasugrel, and noncarriers received clopidogrel. The two primary outcomes were net adverse clinical events - defined as death from any cause, myocardial infarction, definite stent thrombosis, stroke, or major bleeding defined according to Platelet Inhibition and Patient Outcomes (PLATO) criteria - at 12 months (primary combined outcome; tested for noninferiority, with a noninferiority margin of 2 percentage points for the absolute difference) and PLATO major or minor bleeding at 12 months (primary bleeding outcome).ResultsFor the primary analysis, 2488 patients were included: 1242 in the genotype-guided group and 1246 in the standard-treatment group. The primary combined outcome occurred in 63 patients (5.1%) in the genotype-guided group and in 73 patients (5.9%) in the standard-treatment group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.0 to 0.7; PConclusionsIn patients undergoing primary PCI, a CYP2C19 genotype-guided strategy for selection of oral P2Y(12) inhibitor therapy was noninferior to standard treatment with ticagrelor or prasugrel at 12 months with respect to thrombotic events and resulted in a lower incidence of bleeding. (Funded by the Netherlands Organization for Health Research and Development; POPular Genetics ClinicalTrials.gov number, NCT01761786; Netherlands Trial Register number, NL2872.)Patients undergoing primary PCI were randomly assigned to either a genotype-guided strategy for selecting a P2Y(12) inhibitor or to standard treatment with ticagrelor or prasugrel. At 12 months, genotype-guided therapy was noninferior to standard treatment with respect to thrombotic events and resulted in a lower incidence of bleeding.

Background and objectives Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with AKI. Their association with nephrotic syndrome has not been systematically studied. This study aimed to assess the risk of nephrotic syndrome associated with NSAID use. Design, setting, participants, & measurements A matched case-control study was performed in the UK primary care database. Cases were patients with a first diagnosis of nephrotic syndrome and controls were those without nephrotic syndrome. NSAID exposure (grouped either based on cyclooxygenase enzyme selectivity and chemical groups) was classified as either current (use at the nephrotic syndrome diagnosis date and corresponding date in the control group), recent, or past use. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using unconditional logistic regression analysis. Results We included 2620 cases and 10,454 controls. Compared with non-use, current use of 15–28 days and >28 days of conventional NSAIDs was associated with a higher relative risk of nephrotic syndrome: adjusted OR, 1.34; 95% CI, 1.06 to 1.70, and OR, 1.42; 95% CI, 0.79 to 2.55, respectively. Also, recent use (discontinuation 1–2 months before nephrotic syndrome diagnosis date; OR, 1.55; 95% CI, 1.11 to 2.15) and past use (discontinuation 2 months-2 years; OR, 1.24; 95% CI, 1.07 to 1.43), but not current use of 2 years; OR, 0.96; 95% CI, 0.85 to 1.09) were associated with a higher relative risk of nephrotic syndrome as well as past use of selective COX-2 inhibitors (discontinuation 2–24 months; OR, 1.24; 95% CI, 0.98 to 1.58). Categorization based on chemical groups showed that acetic acid and propionic acid derivatives were associated with a higher risk of nephrotic syndrome. Conclusions The use of conventional NSAIDs was associated with a higher risk of nephrotic syndrome starting from at least 2 weeks of exposure, as well as for recent and past exposure up to 2 years before the diagnosis of nephrotic syndrome. This higher risk appeared mainly attributable to acetic acid and propionic acid derivatives.

The reporting of hypersensitivity reactions (HSRs) among non-steroidal anti-inflammatory drugs (NSAIDs) according to cyclooxygenase (COX) selectivity and chemical groups has not been published yet in one study. This study assessed the reporting frequency of HSRs for NSAIDs based on their relative inhibitory potency towards COX enzymes and chemical groups, including the presence/absence of a functional sulfonamide group, in strata of 5 years after market authorization. A case/non-case study was performed among Individual Case Safety Reports (ICSRs) with NSAIDs as suspected drugs in VigiBase, the WHO spontaneous reporting database. Cases were ICSRs mentioning angioedema and anaphylactic/anaphylactoid shock conditions, while non-cases were ICSRs without HSRs. NSAIDs were categorized into (i) NSAIDs with highly COX-2 selectivity (coxibs), (ii) Non-coxib NSAIDs with COX-2 preference, (iii) NSAIDs with poor selectivity, or (iv) NSAIDs with unknown selectivity. Chemical groups were defined based on the Anatomical Therapeutic Chemical classification system and the presence/absence of a functional sulfonamide group. Reporting odds ratios (RORs) and 95% confidence intervals (95% CIs) were calculated using logistic regression analysis. We identified 13,229 cases and 106,444 non-cases. In the first 5 years after marketing, poor selectivity NSAIDs and acetic acid derivatives were associated with the highest ROR of HSRs (age- and sex-adjusted ROR 2.12, 95%CI: 1.98-2.28 and ROR 2.21, 95%CI: 1.83-2.66, respectively), all compared to coxibs, and also sulfonamide NSAIDs compared to non-sulfonamide NSAIDs (age- and sex-adjusted ROR 1.38, 95%CI: 1.29-1.47). After the first 5 years of marketing, most of the RORs returned to approximately 1. This article is protected by copyright. All rights reserved.

Aims Non-steroidal anti-inflammatory drugs (NSAIDs), particularly selective COX-2 inhibitors, are associated with an in-creased risk of cardiovascular adverse events. However, the association between these drugs and out-of-hospitalcardiac arrest with electrocardiogram-documented ventricular tachycardia/ventricular fibrillation (VT/VF-OHCA)has not been studied yet. This study was aimed to evaluate the association between the use of selective COX-2inhibitors or conventional NSAIDs and VT/VF-OHCA compared with non-use .................................................................................................................................................................................................... Methods and results A case–control study was conducted among 2483 cases with VT/VF-OHCA from the AmsteRdam REsuscitationSTudies (ARREST) registry, an ongoing Dutch registry of OHCA, and 10 441 non-VT/VF-OHCA-controls from theDutch PHARMO Database Network, containing drug dispensing records of community pharmacies, over the pe-riod July 2005–December 2011. Up to five controls were matched for age and sex to one case at the date of VT/VF-OHCA (index date). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by conditional logis-tic regression analysis. Of the cases, 0.5% was currently exposed at the index date to selective COX-2 inhibitorsand 2.5% to conventional NSAIDs. Neither current use of selective COX-2 inhibitors nor conventional NSAIDs were associated with an increased risk of VT/VF-OHCA (adjusted OR 1.11, 95% CI: 0.79–1.56 and adjusted OR0.97, 95% CI: 0.86–1.10, respectively) compared with non-use. Stratification for VT/VF-OHCA with presence/ab-sence of acute myocardial infarction did not change these results .................................................................................................................................................................................................... Conclusion Exposure to selective COX-2 inhibitors or conventional NSAIDs was not associated with an increased risk of VT/VF-OHCA compared with non-use.

Background and Purpose: Statins are frequently initiated in patients aged 80 years and older after an ischemic stroke, even though evidence on prevention of recurrent cardiovascular disease is scarce. In this study, we seek evidence for statin prescription in the oldest old. Methods: We performed a retrospective cohort study in patients aged 65 years and older hospitalized for a first ischemic stroke between 1999 and 2016 without statin prescriptions in the year before hospitalization using the Clinical Practice Research Datalink. The age group 65 to 80 years was included to compare our results to current evidence on statin efficacy. The primary outcome was a composite of recurrent stroke, myocardial infarction, and cardiovascular mortality. The secondary outcome was all-cause mortality. A time-varying Cox model was used to account for statin prescription over time. We compared at least 2 years of statin prescription time with untreated and Results: Five thousand nine hundred ten patients, aged 65 years and older were included, of whom 3157 were 80 years and older. Two years of statin prescription in patients aged 80 years and older resulted in both a lower risk of the composite end point (adjusted hazard ratio, 0.80 [95% CI, 0.62–1.02]) and all-cause mortality (adjusted hazard ratio, 0.67 [95% CI, 0.57–0.80]). After correction for the mortality of 23.9% of the patients during the first 2 years, the number needed to treat was 64 for the primary outcome during a median follow-up of 3.9 years and 19 for all-cause mortality. Conclusions: Statins initiated in patients aged 80 and older, discharged home after hospitalization for an ischemic stroke are associated with a reduction in cardiovascular events.

Aims Drug exposure status based on routinely collected data might be misclassified when the database contains only prescriptions from 1 type of prescriber (e.g. general practitioner and not specialist). This study aims to quantify the impact of such exposure misclassification on the risk of major bleeding and stroke/transient ischaemic attack (TIA)associated with direct oral anticoagulants (DOACs) vs. vitamin K antagonists (VKAs). Methods Incident anticoagulant users (>12 mo free of anticoagulation use) in the Dutch PHARMO Database Network between 2008 and 2017 were included. Drug exposure was assessed using pharmacy dispensing information. The risks of hospital admission of major bleeding for DOAC vs. VKA users was assessed with Cox regression analysis, where exposure was based on all dispensings, on general practitioner (GP)-prescribed dispensings only or on specialist-prescribed dispensings only. Hazard ratios (HRs) were estimated also for hospitalization for gastrointestinal bleeding, intracranial bleeding and stroke/TIA. Results We included 99 182 VKA-initiators and 21 795 DOAC-initiators. Use of DOAC was associated with a lower risk of major bleeding compared to VKA use; HR 0.79 (95% confidence interval 0.70-0.90), 0.78 (0.68-0.91) and 0.62 (0.50-0.76), for exposure based on complete dispensing information, only GP- and only specialist-prescribed dispensings, respectively. Similar results were found for the other bleeding outcomes. For stroke/TIA the HRs were 0.96 (0.84-1.09), 1.00 (0.84-1.18) and 0.72 (0.58-0.90), respectively. Conclusion Including only GP-prescribed anticoagulant dispensings in this case did not materially impact the effect estimates compared to including all anticoagulant dispensings. Including only specialist-prescribed dispensings, however, strengthened the effect estimates.

Underlying genetic determinants contribute to developing type 2 diabetes (T2D) future diseases. The present study aimed to identify which genetic variants are associated with the incident of the major T2D co-morbid disease. First, we conducted a discovery study by investigating the genetic associations of comorbid diseases within the framework of the Utrecht Cardiovascular Pharmacogenetic studies by turning information of > 25 years follow-up data of 1237 subjects whom were genotyped and included in the discovery study. We performed Cox proportional-hazards regression to examine associations between genetic variants and comorbid diseases including cardiovascular diseases (CVD), chronic eye disease, cancer, neurologic diseases and chronic kidney disease. Secondly, we replicated our findings in two independent cohorts consisting of 1041 subjects. Finally, we performed a meta-analysis by combining the discovery and two replication cohorts. We ascertained 390 (39.7%) incident cases of CVD, 182 (16.2%) of chronic eye disease, 155 (13.8%) of cancer, 31 (2.7%) of neurologic disease and 13 (1.1%) of chronic kidney disease during a median follow-up of 10.2 years. In the discovery study, we identified a total of 39 Single Nucleotide Polymorphisms (SNPs) associated with comorbid diseases. The replication study, confirmed that rs1870849 and rs8051326 may play a role in the incidence of chronic eye disease in T2D patients. Half of patients developed at least one comorbid disease, with CVD occurring most often and earliest followed by chronic eye disease. Further research is needed to confirm the associations of two associated SNPs with chronic eye disease in T2D.

Aims: Thiopurines are important for treating inflammatory bowel disease, but are often discontinued due to adverse effects. Concomitant use of allopurinol might lower the risk of these unwanted effects, but large studies in the general population are lacking. The aims of this study were to evaluate rates of hepatotoxicity, myelotoxicity, pancreas toxicity and therapy persistence in adult thiopurine users with or without allopurinol. Methods: A retrospective population-based cohort study was conducted within current thiopurine users (Clinical Practice Research Datalink). Among these patients, co-use of allopurinol was compared to non-use. Hazard ratios (HRs) for hepatotoxicity, myelotoxicity and pancreatitis were derived using time-dependent Cox proportional hazards models, and were adjusted for potential confounders. Persistence of thiopurine use was evaluated using Log-rank statistics. Results: Patients using thiopurines (n = 37 360) were identified of which 1077 were concomitantly taking allopurinol. A 58% decreased risk of hepatotoxicity was observed in those concomitantly taking allopurinol (HR 0.42; 95% CI 0.30–0.60; NNT 46). Rate of myelotoxicity (HR 0.96; 95% CI 0.89–1.03) was not influenced. Risk of pancreatitis was increased (HR 3.00; 95% CI 1.01–8.93; NNH 337), but was only seen in those with active gout (suggesting confounding by indication). Finally, allopurinol co-users were able to maintain thiopurine therapy over twice as long as those not on allopurinol (3.9 years vs. 1.8 years, P < 0.0001). Conclusion: In thiopurine users, allopurinol is associated with a 58% reduced risk of hepatotoxicity. In addition, thiopurine persistence was prolonged by 2.1 years in allopurinol users. These data support the use of allopurinol in individuals requiring thiopurine therapy.

Aims: To study community pharmacists' level of knowledge on medication safety in patients with hepatic impairment and their practice in caring for these patients. Methods: Pharmacists from Dutch community pharmacies (n = 1545) were invited to participate in an online survey. The survey consisted of 27 questions covering 2 main topics: knowledge and current practice. The level of knowledge was measured by a 6-item knowledge test. Multiple linear regression was used to identify predictors of correctly answered responses. Results: In total, 338 pharmacists (22%) completed the questionnaire. The mean knowledge score was 2.8 (standard deviation 1.6). Only 30.3% of respondents were able to appropriately advise on use of analgesics in severe cirrhosis. Postgraduate education on hepatic impairment, knowledge of recently developed practical guidance, and fewer years of practice were associated with a higher level of knowledge. In total, 70.4% indicated to evaluate medication safety in a patient with hepatic impairment at least once weekly. In the past 6 months, 83.3% of respondents consulted a prescriber about a patient with hepatic impairment. Frequently encountered barriers in practice were insufficient knowledge on the topic and a lack of essential patient information (i.e. diagnosis and severity of the impairment). Conclusion: Community pharmacists regularly evaluate the safety of medication in patients with hepatic impairment, yet their level of knowledge was insufficient and additional education is needed. Pharmacists experienced several difficulties in providing pharmaceutical care. If these issues are resolved, pharmacists can play a more active role in ensuring medication safety in their patients with hepatic impairment.

Increased global longevity requires a re-evaluation of current structures in society to adapt to the consequential demographic shift. As (very) old people are prone to impaired human organ and body functions resulting in, for example, multimorbidity, polypharmacy, hospitalisation and problems in medication management, it is increasingly acknowledged that re-evaluations should include the suitability of pharmaceutical patient care as one of the cornerstones of public health. Following the 2011 European Medicines Agency (EMA) Geriatric Strategy, in 2017 the EMA published the draft "Reflection paper on the pharmaceutical development of medicines for use in the older population". The draft paper was opened for public consultation and specific attention and feedback (either supportive or with a proposal for revision) was asked on three design aspects: tablet breaking, drug administration through enteral feeding tubes and medication management. Following publication, the draft paper was presented at two public conferences attended by participants from different disciplines. This manuscript is intended to draw the attention of different stakeholder parties to the urgent need to collaborate on the emerging issues arising from increasing longevity and multimorbidity, and especially those associated with pharmaceutical patient care and drug product design, including the need for collaborative research into existing or emerging knowledge gaps. The manuscript focuses on the three aforementioned aspects of pharmaceutical development (tablet breaking, drug administration through enteral feeding tubes and medication management) as these highly relate to medication safety and efficacy and constitute persistent and typical challenges for older people, caregivers and healthcare professionals in daily clinical practice.

Purpose The antiarrhythmic drug amiodarone has a long half‐life of 60 days, which is often ignored in observational studies. This study aimed to investigate the impact of different exposure definitions on the association between amiodarone use and the risk of acute pancreatitis. Method Using data from the Dutch PHARMO Database Network, incident amiodarone users were compared to incident users of a different type of antiarrhythmic drug. Eighteen different definitions were applied to define amiodarone exposure, including dichotomized, continuous and categorized cumulative definitions with lagged effects to account for the half‐life of amiodarone. For each exposure definition, a Cox proportional hazards model was used to estimate the hazard ratio (HR) of hospitalization for acute pancreatitis. Results This study included 15,378 starters of amiodarone and 21,394 starters of other antiarrhythmic drugs. Adjusted HRs for acute pancreatitis ranged between 1.21−1.43 for dichotomized definitions of exposure to amiodarone, between 1.13‐1.22 for dose definitions (per DDD) and between 0.52‐1.72 for cumulative dose definitions, depending on the category. Accounting for lagged effects had little impact on estimated HRs. Conclusions This study demonstrates the relative insensitivity of the association between amiodarone and the risk of acute pancreatitis against a broad range of different exposure definitions. Accounting for possible lagged effects had little impact, possibly because treatment switching and discontinuation was uncommon in this population.

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.

Background: Little is known about outcomes of adjuvant-treated melanoma patients beyond the clinical trial setting. Since 2019, adjuvant-treated melanoma patients have been registered in the DMTR, a population-based registry to monitor the quality and safety of melanoma care in the Netherlands. This study aims to describe treatment patterns, relapse, and toxicity rates of adjuvant-treated melanoma patients beyond the clinical trial setting.Methods: Analyses were performed on adjuvant-treated melanoma patients included in the DMTR. Descriptive statistics were used to analyse patient-, and treatment characteristics. A baseline registration completeness analysis was performed, and an analysis on trial eligibility in clinical practice patients. Recurrence-free survival (RFS) at 12-months was estimated with the Kaplan-Meier method.Results: A total of 641 patients were treated with adjuvant anti-PD-1 therapy. RFS at 12-months was 70.6% (95% CI, 66.9-74.6) with a median follow-up of 12.8 months. Sex, stage of disease and Breslow thickness were associated with a higher hazard for RFS. Eighteen per cent of the anti-PD-1-treated patients developed grade >= 3 toxicity. Sixty-one per cent of patients prematurely discontinued anti-PD-1 therapy.Conclusion: Adjuvant anti-PD-1 treatment of resected stage III/IV melanoma in daily practice showed slightly higher toxicity rates and more frequent premature discontinuation but similar RFS rates compared to trials. (C) 2021 The Authors. Published by Elsevier Ltd.

This study systematically reviewed and quantified the relationship between exposure to antibiotics during the first 2 years of life and the risk of allergies/atopies including hay fever, eczema, food allergy, positive skin prick testing (SPT) or elevated allergen-specific serum/plasma immunoglobulin (Ig) E levels later in life. PubMed and Web of Science databases were searched for observational studies published from January 1966 through November 11, 2015. Overall pooled estimates of the odds ratios (ORs) were obtained using fixed or random-effects models. Early life exposure to antibiotics appears to be related with an increased risk of allergic symptoms of hay fever, eczema and food allergy later in life. The summary OR for the risk of hay fever (22 studies) was 1.23, 95% confidence interval (CI):1.13-1.34; I(2) : 77.0%. The summary OR for the risk of eczema (22 studies) was 1.26, 95% CI: 1.15-1.37; I(2) : 74.2% and the summary OR for food allergy (3 studies) was 1.42, 95% CI: 1.08-1.87; I(2) : 80.8%. However, no association was found for antibiotics exposure early in life and objective atopy measurements including positive SPT or elevated allergen-specific serum/plasma IgE levels. This article is protected by copyright. All rights reserved

Purpose The aim of this study is to investigate the role of health-related quality-of-life (QoL) data in relative effectiveness assessments (REAs) of new anti-cancer drugs across European jurisdictions, during health technology assessment procedures. Methods Comparative analysis of guidelines and publicly available REAs in six European jurisdictions of anti-cancer drugs approved by EMA between 2011 and 2013. Results Fourteen anti-cancer drugs were included, adding up to 79 REAs. Whilst all guidelines state that QoL is a relevant endpoint to determine the relative effectiveness of new cancer drugs, QoL data were included in only 54% of the 79 reports and their impact on the recommendations was limited. Conclusions Whilst national guidelines recognize the relevance of QoL to determine the relative effectiveness of new anti-cancer drugs, this is not well-reflected in current assessments. Developing and implementing into REAs specific evidence requirements for QoL data would improve the use of this patient-centred outcome in future reimbursement and pricing decisions.

Background Despite increasing recognition of the value of real-world data (RWD), consensus on the definition of RWD is lacking. Objectives To review definitions publicly available for RWD to shed light on similarities and differences between them. Methods A literature review and stakeholder interviews were used to compile data from eight groups of stakeholders. Data from documents and interviews were subjected to coding analysis. Definitions identified were classified into four categories: 1) data collected in a non-randomized controlled trial setting, 2) data collected in a non-interventional/non-controlled setting, 3) data collected in a non-experimental setting, and 4) others (i.e., data that do not fit into the other three categories). The frequency of definitions identified per category was recorded. Results Fifty-three documents and 20 interviews were assessed. Thirty-eight definitions were identified: 20 out of 38 definitions (53%) were category 1 definitions, 9 (24%) were category 2 definitions, 5 (13%) were category 3 definitions, and 4 (11%) were category 4 definitions. Differences were identified between, and within, definition categories. For example, opinions differed on the aspects of intervention with which non-interventional/non-controlled settings should abide. No definitions were provided in two interviews or identified in 33 documents. Conclusions Most of the definitions defined RWD as data collected in a non-randomized controlled trial setting. A considerable number of definitions, however, diverged from this concept. Moreover, a significant number of authors and stakeholders did not have an official, institutional definition for RWD. Persisting variability in stakeholder definitions of RWD may lead to disparities among different stakeholders when discussing RWD use in decision making.

Objectives To identify single nucleotide polymorphisms (SNPs) associated with switching from an angiotensin-converting enzyme (ACE)-inhibitor to an angiotensin receptor blocker. Methods Two cohorts of patients starting ACE-inhibitors were identified within the Rotterdam Study in the Netherlands and the Genetics of Diabetes Audit and Research in Tayside Scotland study in Scotland. Cases were intolerant patients who switched from an ACE-inhibitor to an angiotensin receptor blocker and controls were individuals who used ACE-inhibitors continuously for at least 2 years and did not switch. Genome-wide association study (GWAS) using an additive model was run in these sets and the results were meta-analysed using Genome-Wide Association Meta Analysis software. Results A total of 972 cases out of 5161 ACE-inhibitor starters were identified. Eight SNPs within four genes reached the genome-wide association study significance level (P

Objectives: European regulations do not allow modification or waiver of informed consent for medicines randomized controlled trials (RCTs) where the three 2016 Council for International Organizations of Medical Sciences (CIOMS) provisions are met (consent would be impractical or unfeasible, yet the trial would have high social value and pose no or minimal risk to participants). We aimed to identify whether any such trials of medicines were being conducted in Europe.Study Design and Setting: This is a survey of all phase 4 "ongoing" RCTs on the EU clinical trial register between July 1, 2016 and June 30, 2018, to identify those with potentially high levels of pragmatism. Trials that were excluded were as follows: those conducted on rare diseases; conducted on healthy volunteers (except those assessing vaccines); masked (single-, double-blind) trials; single-center trials; those where one could expect to lead patients to prefer one intervention over the other; and miscellaneous reasons. The degree of pragmatism of the RCTs was self-assessed by trials' investigators by means of the PRECIS-2 tool. Investigators of those trials considered to be highly pragmatic assessed the fulfillment of the three CIOMS provisions. Seven patients assessed the social value of the RCTs. Finally, 33 members of 11 research ethics committees (RECs) assessed the social value of the trials and whether they posed no more than minimal risk to participants. Investigators, patients, and REC members assessed the fulfillment of the CIOMS provisions as "yes," "not sure" or "no."Results: Of the 638 phase 4 trials, 420 were RCTs, and 21 of these (5%) were candidates to be pragmatic. Investigators of 15 of these 21 RCTs self-assessed their trial's degree of pragmatism: 14 were highly pragmatic. Of these 14, eight fulfilled the three CIOMS provisions. Assessments by patients and RECs were inconsistent for several trials.Conclusions: We found few low-risk participant-level pragmatic RCTs that could be suitable for modified or waived participants' informed consent. European regulators should consider amending the current regulation and encouraging the conduct of such trials. (C) 2019 Elsevier Inc. All rights reserved.

Clinical trial regulations should remove unnecessary obstacles for the conduct of pragmatic trials assessing the comparative effectiveness of medicines posing no or minimal risk to participants, say Rafael Dal-Re and colleagues

Background: Conditional financing (CF) of hospital drugs was implemented in the Netherlands as a form of managed entry agreements between 2006 and 2012. CF was a 4-year process comprising 3 stages: initial health technology assessment of the drug (T = 0), conduct of outcomes research studies, and reassessment of the drug (T = 4). Objectives: To analyze stakeholder experiences in implementing CF in practice. Methods: Public and private stakeholders were approached for participation in stakeholder interviews through standardized email invitations. An interview guide was developed to guide discussions that covered the following topics: perceived aims of CF, functioning of CF, impact of CF, and conclusions and future perspectives. Extensive summaries were generated for each interview and subsequently used for directed content analysis. Results: Thirty stakeholders were interviewed. Differences emerged among the stakeholders on the perceived aims of CF. Conversely, there was some agreement among stakeholders on the shortcomings in the functioning of CF, the positive impact of CF on the Dutch healthcare setting, and improvement points for CF. Conclusions: Despite stakeholders' belief that CF either did not meet its aims or only partially did so, there was agreement on the need for new policy to address the same aims of CF in the future. Nevertheless, stakeholders diverged on whether CF should be improved on the basis of learnings identified and reintroduced into practice or replaced with new policy schemes.

PURPOSE: To estimate the effectiveness and safety of direct oral anticoagulants (DOACs) compared with warfarin in AF patients with type 2 diabetes (T2DM). METHODS: A retrospective cohort study was designed, using the UK Clinical Practice Research Datalink (August 2011 - June 2018). Participants were 1-year naïve users of DOACs or warfarin, followed from the date of first prescription of an oral anticoagulant until the end of the study period, death, discontinuation of treatment, switching to another anticoagulant, or an outcome of interest, whichever came first. Cox regression analysis was performed to estimate the hazard ratio (HR) adjusted for potential confounders. RESULTS: A total of 8,555 patients were identified. No significant differences were found between DOACs and warfarin in the risk of stroke (adjusted HR 1.15; 95% CI 0.82 - 1.60), ischemic and unspecified stroke (adjusted HR 1.23; 95% CI 0.86 - 1.76) or haemorrhagic stroke (adjusted HR 0.75; 95% CI 0.30 - 1.85), and myocardial infarction (adjusted HR 1.39 ;95% CI 0.99 - 1.97). DOAC and warfarin users were comparable with respect to risk of major bleed (adjusted HR 0.83; 95% CI 0.68 - 1.03), intracranial bleeding (HR 0.66; 95% CI 0.34 - 1.30), gastrointestinal bleeding (HR 0.88; 95% CI 0.60 - 1.30), and bleeding on other clinically relevant sites (HR 0.89; 95% CI 0.60 - 1.31). In the subgroup analyses stratified by gender and diabetes severity, the risk for stroke and bleeding remained consistent. CONCLUSION: DOACs are effective and safe alternatives to warfarin for the prevention of stroke in AF patients with T2DM.

Aims The aims of the present study were to assess antiplatelet drug use patterns after a first myocardial infarction (MI) and to evaluate the determinants of antiplatelet nonpersistence. Methods The present study was conducted in 4690 patients from the Utrecht Cardiovascular Pharmacogenetics cohort with a first MI between 1986 and 2010, who were followed for a maximum of 10 years. Medication use and event diagnosis were obtained from the Dutch PHARMO Record Linkage System. Antiplatelet drug users were classified as persistent users (gap between prescriptions ≤90 days), nonpersistent users (>90‐day gap and no refills), and restarters (a new prescription after a >90‐day gap). The association between potential determinants and antiplatelet nonpersistence was analysed using Cox regression. Results The proportions of persistent users decreased from 84.0% at the 1‐year follow‐up to 32.8% at 10 years for any antiplatelet drug, and 77.3% to 27.5% for aspirin; and 39.0% to 6.4% for clopidogrel at 6 years. Most nonpersistent users restarted antiplatelet drugs later, leading to 89.3% overall antiplatelet drug users at 10 years after MI. Diabetes (hazard ratio [HR] 0.44; 0.32–0.60), hypertension (HR 0.77; 0.60–0.99), hypercholesterolaemia (HR 0.49; 0.39–0.62) and more recent MI diagnosis period (2003–2007: HR 0.69, 0.61–0.79; 2008–2010: HR 0.38, 0.19–0.77, compared to ≤ 2002 period) lowered the risk of antiplatelet nonpersistence, while vitamin K antagonist (VKA) comedication (HR 18.97; 16.91–21.28) increased this risk. Conclusions A large proportion of patients with a first MI still used antiplatelet drugs after 10 years. The frequent discontinuations during this time frame are expected to reduce the effectiveness of antiplatelet drugs as secondary prevention of cardiovascular diseases. Diabetes, hypertension, hypercholesterolaemia, VKA comedication and MI diagnosis period were determinants of antiplatelet nonpersistence.

Contains fulltext : 225357.pdf (Publisher’s version ) (Closed access) AIMS: Tablets may be subdivided for dose adaptations or to ease swallowing. The handling is common in older patients but can be difficult and inaccurate. Currently, it is not known which hand-eye functions determine the ability of older people to break tablets by hand and to do so with acceptable ease and accuracy. The aim of this study was to develop a test battery to assess the hand-eye functions relevant in predicting easy and accurate tablet subdivision in older people. METHODS: A mixed methods study was conducted including literature reviews and a pilot experiment. The reviews were conducted in Pubmed, Google Scholar, Dutch journals and professional standards. The first review tried to identify the hand-eye functions relevant to tablet subdivision and the second the associated measuring instruments, testing protocols and normative data. A test battery was empanelled. A pilot experiment was conducted in 30 adult volunteers to optimize and evaluate the test battery. RESULTS: Five domains were considered relevant: hand size, hand strength, flexibility/manual dexterity, vision and coordination. Hand size could best be measured by finger circumference, hand strength by pinch- and grip strength, flexibility by active range of joint motion, manual dexterity (and flexibility, coordination, cognition, vision) by pegboard function, vision by near visual acuity. Older people preferred the use of tablet splitters over hand breaking. CONCLUSION: Easy and accurate tablet subdivision is essential to the good use of medicines. We developed a test battery for older people, but probably of value to all age groups.

Summary What is known and objective Important risk factors and over‐the‐counter (OTC) dispensing of non‐steroidal anti‐inflammatory drugs (NSAIDs) are often not routinely recorded in electronic health records. This study aimed to assess the impact of patient's reports on these factors on the risk of acute myocardial infarction (AMI) for NSAID use. Methods A nested case‐control study was conducted among adults in the Utrecht Cardiovascular Pharmacogenetics study. Cases were patients with a first diagnosis of AMI as a hospital discharge diagnosis and controls were those without AMI. NSAID exposure was either current use of selective COX‐2 inhibitors or conventional NSAIDs. Information was collected from The Dutch PHARMO Database Network (pharmacy records of drug dispensing linked to hospitalization records) and the patient's questionnaire (lifestyle factors, body mass index and history of cardiovascular diseases). Unconditional logistic regression analysis was used to calculate odds ratios (ORs) and to control for confounding factors. Results We identified 970 AMI cases and 2974 controls. Among cases, 11 (1.1%) and 185 (19.1%) were exposed to selective COX‐2 inhibitors and conventional NSAIDs, respectively. Compared to non‐use, none of these drug classes were associated with an increased risk of AMI (adjusted OR 1.07, 95% CI: 0.52‐2.18 and 0.93, 95% CI: 0.77‐1.12, respectively). Additional adjustment for potential confounders from patient's reports did not change the risk estimates (adjusted OR 1.08, 95% CI: 0.53‐2.22 and 0.89, 95% CI: 0.73‐1.09, respectively). What is new and conclusion Additional confounding control for variables from self‐reported data or considering self‐reported OTC NSAID use did not change the risk estimates for the association between NSAIDs and AMI.

Background Reimbursement decisions are conventionally based on evidence from randomised controlled trials (RCTs), which often have high internal validity but low external validity. Real-world data (RWD) may provide complimentary evidence for relative effectiveness assessments (REAs) and cost-effectiveness assessments (CEAs). This study examines whether RWD is incorporated in health technology assessment (HTA) of melanoma drugs by European HTA agencies, as well as differences in RWD use between agencies and across time. Methods HTA reports published between 1 January 2011 and 31 December 2016 were retrieved from websites of agencies representing five jurisdictions: England [National Institute for Health and Care Excellence (NICE)], Scotland [Scottish Medicines Consortium (SMC)], France [Haute Autorité de santé (HAS)], Germany [Institute for Quality and Efficacy in Healthcare (IQWiG)] and The Netherlands [Zorginstituut Nederland (ZIN)]. A standardized data extraction form was used to extract information on RWD inclusion for both REAs and CEAs. Results Overall, 52 reports were retrieved, all of which contained REAs; CEAs were present in 25 of the reports. RWD was included in 28 of the 52 REAs (54%), mainly to estimate melanoma prevalence, and in 22 of the 25 (88%) CEAs, mainly to extrapolate long-term effectiveness and/or identify drug-related costs. Differences emerged between agencies regarding RWD use in REAs; the ZIN and IQWiG cited RWD for evidence on prevalence, whereas the NICE, SMC and HAS additionally cited RWD use for drug effectiveness. No visible trend for RWD use in REAs and CEAs over time was observed. Conclusion In general, RWD inclusion was higher in CEAs than REAs, and was mostly used to estimate melanoma prevalence in REAs or to predict long-term effectiveness in CEAs. Differences emerged between agencies’ use of RWD; however, no visible trends for RWD use over time were observed. Electronic supplementary material The online version of this article (10.1007/s40273-017-0596-z) contains supplementary material, which is available to authorized users.

Background As proprotein convertase subtilisin-kexin type 9 (PCSK9) monoclonal antibodies are entering the market, we assessed the cost-effectiveness of PCSK9 inhibition added to standard lipid-lowering therapy in patient groups at high risk for major adverse cardiovascular events (MACE). Methods A lifetime Markov Model was designed to estimate healthcare costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) for PCSK9 inhibition added to standard therapy in patients with Familial Hypercholesterolemia (FH), patients with vascular disease at high MACE recurrence risk, and patients with vascular disease with diabetes mellitus. The balance between costs and health outcomes was established for a broad range of potential relative risk reductions and drug costs. Results The expected QALY gain per patient and ICER in the main scenario were 1.4 QALYs for €78,485/QALY gained in patients with FH, 0.22 QALYs for €176,735/QALY gained in those with vascular disease and a predicted risk of MACE ≥30% in 10years, and 0.22 QALYs for €295,543/QALY gained in those with vascular disease and diabetes. Results were sensitive to assumptions on PCSK9 inhibitor treatment efficacy, and vascular event risks. Conclusion The costs and effects of PCSK9 inhibition added to standard lipid-lowering treatment in patient groups at high risk for MACE can be estimated and adapted to a specific clinical setting. PCSK9 inhibition could be cost-effective in patients with FH. In patients with vascular disease PCSK9 inhibition is less cost-effective, however, a price development may change clinical practice. This model may aid treatment and reimbursement decisions regarding PCSK9 inhibitors.

AIMS: The aims of the present study were, firstly, to evaluate long‐term trends in the occurrence and treatment of cardiovascular disease (CVD) risk factors and the occurrence of CVD events in children with type 1 diabetes mellitus (T1DM) and, secondly, to assess the determinants of undertreatment of CVD risk factors. METHODS: A retrospective cohort study was conducted in 3728 children (

Insufficient professional development may lead to poor performance of healthcare professionals. Therefore, continuing education (CE) and continuing professional development (CPD) are needed to secure safe and good quality healthcare. The aim of the study was to investigate the hypothesized associations and their directions between pharmacists’ basic psychological needs in CE, their academic motivation, well-being, learning outcomes. Self-determination theory was used as a theoretical framework for this study. Data were collected through four questionnaires measuring: academic motivation, basic psychological needs (BPN), vitality and lifelong learning adaptability of pharmacists in the CE/CPD learning context. Structural equation modelling was used to analyze the data. Demographic factors like gender and working environment influenced the observed scores for frustration of BPN and factors like training status and working experience influenced the observed scores for academic motivation. A good model fit could be found only for a part of the hypothesized pathway. Frustration of BPN is positively directly related to the less desirable type of academic motivation, controlled motivation (0.88) and negatively directly related to vitality (− 1.61) and negatively indirectly related to learning outcomes in CE. Fulfillment or frustration of BPN are important predictors for well-being and learning outcomes. Further research should be conducted to discover how we can prevent these needs from being frustrated in order to design a motivating, vitalizing and sustainable CE/CPD system for pharmacists and other healthcare professionals. Basic psychological needs are very important predictors for well-being and learning outcomes. Further research should be conducted to discover how we can prevent these needs from being frustrated in order to design a motivating, vitalizing and sustainable CE/CPD system for pharmacists and other healthcare professionals.

Objective To assess the impact on noninferiority decisions when using a single margin or single preserved fraction (PF) for all noninferiority trials within a pharmacological class. Study Design and Setting A search in PubMed, EMBASE, and CENTRAL resulted in seven active-controlled statin trials (nine noninferiority comparisons) for treating hyperlipidemia. The impact of using a single margin was assessed by calculating whether this margin corresponds to different PFs among comparator statins which will demonstrate that the threshold of demonstrating noninferiority (in terms of the PF) varies among comparator statins. The use of a single PF was assessed by reanalyzing noninferiority in the included trials with new margins (based on the single PF) for each comparator statin. Results The use of a single margin resulted in PFs that range between 81% and 89% for the different comparators (i.e., different thresholds). The use of a single PF resulted in four of nine (44%) different noninferiority conclusions compared with the original analyses. Conclusion The threshold of demonstrating noninferiority with a single margin or single PF of the effect per pharmacological class may not be consistent with using a margin/PF for each comparator separately and may impact the conclusions of noninferiority.

Objective. To explore the changes in motivation of Dutch pharmacists for Continuing Education (CE) in the Dutch CE system. Methods. Pharmacists’ motivation was measured across three time points with the Academic Motivation Scale, based on the Self-Determination Theory of motivation. The Latent Growth Modelling technique was used to analyze these data. Results. Over a period of 21 months, Controlled Motivation had increased and Relative Autonomous Motivation of Dutch pharmacists had decreased. Traineeship was the only demographic factor with a significant influence on the change in motivation. No subgroups with different trajectories could be identified. Conclusion. Relative Autonomous Motivation of Dutch pharmacists for CE decreases over time. This indicates a loss of Autonomous Motivation (“good” motivation) in favor of Controlled Motivation (“bad” motivation). Further research needs to be conducted to gain a better understanding of the association between pharmacist motivation and the features of the current CE system.

The purpose of this study was to assess the impact of age and sex on the reporting of cough and angioedema related to renin angiotensin system (RAS) inhibitors. A case/non-case study was performed in VigiBase. Two case groups were identified, reports of cough and reports of angioedema and non-cases were all reports of all other adverse events. Logistic regression analysis was used to assess the association between reporting of cough and angioedema with each class of RAS inhibitors stratified by age/sex and to control for confounding. The reporting of cough with angiotensin-converting enzyme (ACE) inhibitors was significantly higher in women than in men (adjusted-ROR: 44.0, 95%CI (43.2-44.8) for women versus 29.2, 95%CI (28.5-29.9) for men). There was no difference in reporting of cough linked to angiotensin receptor blockers (ARBs) and aliskiren between men and women. In contrast, the reporting of angioedema with ACE inhibitors and ARBs was significantly higher in men than in women but for aliskiren, women had a significantly higher ROR than men (adjusted-ROR: 5.20, 95%CI (4.18-6.46) for women versus 3.04, 95%CI (2.30-4.02) for men). The reporting of cough with ACE inhibitors was increased with age until reaching a plateau at middle adulthood (40-59 years) and the reporting of angioedema with ACE inhibitors was increased with age until elderly (60-79 years). Age had only a slight effect on the reporting of cough and angioedema with ARBs and aliskiren. Both age and sex have substantial effects on the reporting of cough and angioedema with RAS inhibitors and in particular ACE inhibitors. Further study is needed to determine whether these differences mainly express different ADR risks in subgroups or also can be explained by factors influencing reporting. This article is protected by copyright. All rights reserved.

OBJECTIVES: To investigate the 5-yr prevalence and incidence rates of cardiovascular medication and cardiovascular disease before and after onset of type 1 diabetes (T1D) in children and adolescents. METHODS: Children and adolescents (

Introduction: Little is known about the overall quality of life (QOL) in patients newly diagnosed with venous thromboembolism (VTE) and atrial fibrillation (AF). We studied QOL in patients with VTE and AF immediately after the start of anticoagulant therapy, and after three months of treatment. Furthermore we identified whether QOL was affected by age, gender and nationality. Materials and Methods: The European pharmacogenetics of anticoagulant therapy (EU-PACT) study was a multicentre, randomized controlled trial of patients aged > 18 years diagnosed with VTE or AF. QOL was assessed using EuroQol 5 dimensions (EQ-5D) questionnaires. Results: The EQ-5D questionnaires were completed by 187 patients with VTE and 660 patients with AF. The QOL in patients diagnosed with VTE or AF was significantly impaired, however, during a 3 months treatment period, patients experienced an improvement (p < 0.05). The QOL in patients diagnosed with VTE improved with increasing age, with similar effects seen in men and women. Men and women diagnosed with AF differed in QOL (respectively 0.84 and 0.74, p < 0.05), and QOL decreased with age. Comparison between countries showed significant differences in the EQ-Index score at follow-up of patients with VTE, and in both EQ-Index score and EQ-VAS of patients with AF. Conclusions: The QOL in patients with VTE and AF is strongly reduced directly after the start of anticoagulant treatment, but improves within 3 months. Moreover, QOL is influenced by demographic and disease-specific variables. These findings provide useful information for future cost-effectiveness studies.

Objectives: Haloperidol may prolong ECG QTc-duration but is often prescribed perioperatively to hip-fracture patients. We aimed to determine (1) how QTc-duration changes perioperatively, (2) whether low-dose haloperidol-use influences these changes, and (3) which clinical variables are associated with potentially dangerous perioperative QTc-prolongation (PD-QTc; increase >50 ms or to >500 ms).Design: Prospective cohort study.Setting: Tertiary university teaching-hospital.Participants: Patients enrolled in a randomized controlled clinical trial of melatonin versus placebo on occurrence of delirium in hip-fracture patients.Measurements: Data from ECGs made before and after hip surgery (1–3 days and/or 4–6 days post-surgery) were analyzed. QTc-duration was measured by hand, blinded for haloperidol and pre/post-surgery status. Clinical variables were measured at baseline. Mixed model analysis was used to estimate changes in QTc-duration. Risk-factors for PD-QTc were estimated by logistic regression analysis.Results: We included 89 patients (mean age 84 years, 24% male); 39 were treated with haloperidol. Patients with normal pre-surgery QTc-duration (male ≤430 ms, female ≤450 ms) had a significant increase (mean 12 ms, SD 28) in QTc-duration. A significant decrease (mean 19 ms, SD 34) occurred in patients with prolonged pre-surgery QTc-duration (male >450ms, female >470 ms). Haloperidol-use did not influence the perioperative course of the QTc-interval (p=0.351). PD-QTc (n=8) was not associated with any of the measured risk-factors.Conclusion: QTc-duration changed differentially, increasing in patients with normal, but decreasing in patients with abnormal baseline QTc-duration. PD-QTc was not associated with haloperidol-use or other risk-factors. Low-dose oral haloperidol did not affect perioperative QTc-interval.

Objectives Findings from nonrandomized studies on safety or efficacy of treatment in patient subgroups may trigger postlaunch randomized clinical trials (RCTs). In the analysis of such RCTs, results from nonrandomized studies are typically ignored. This study explores the trade-off between bias and power of Bayesian RCT analysis incorporating information from nonrandomized studies. Study Design and Setting A simulation study was conducted to compare frequentist with Bayesian analyses using noninformative and informative priors in their ability to detect interaction effects. In simulated subgroups, the effect of a hypothetical treatment differed between subgroups (odds ratio 1.00 vs. 2.33). Simulations varied in sample size, proportions of the subgroups, and specification of the priors. Results As expected, the results for the informative Bayesian analyses were more biased than those from the noninformative Bayesian analysis or frequentist analysis. However, because of a reduction in posterior variance, informative Bayesian analyses were generally more powerful to detect an effect. In scenarios where the informative priors were in the opposite direction of the RCT data, type 1 error rates could be 100% and power 0%. Conclusion Bayesian methods incorporating data from nonrandomized studies can meaningfully increase power of interaction tests in postlaunch RCTs.

Aim: To assess the required characteristics (cost, sensitivity and specificity) of a pharmacogenomic test for being a cost-effective prevention of angiotensin-converting enzyme inhibitors induced angioedema. Furthermore, we assessed the influence of only testing high-risk populations. Materials & methods: A decision tree was used. Results: With a willingness-to-pay threshold of (sic)20,000 and (sic)80,000 per quality adjusted life year, a 100% sensitive and specific test may have a maximum cost of (sic)1.30 and (sic)1.95, respectively. When only genotyping high-risk populations, the maximum test price would be (sic)5.03 and (sic)7.55, respectively. Conclusion: This theoretical pharmacogenomic test is only cost-effective at high specificity, high sensitivity and a low price. Only testing high-risk populations yields more realistic maximum test prices for cost-effectiveness of the intervention

Background: Randomized controlled trials provide robust data on the efficacy of interventions rather than on effectiveness. Health technology assessment (HTA) agencies worldwide are thus exploring whether real-world data (RWD) may provide alternative sources of data on effectiveness of interventions. Presently, an overview of HTA agencies' policies for RWD use in relative effectiveness assessments (REA) is lacking. Objectives: To review policies of six European HTA agencies on RWD use in REA of drugs. A literature review and stakeholder interviews were conducted to collect information on RWD policies for six agencies: the Dental and Pharmaceutical Benefits Agency (Sweden), the National Institute for Health and Care Excellence (United Kingdom), the Institute for Quality and Efficiency in Healthcare (Germany), the High Authority for Health (France), the Italian Medicines Agency (Italy), and the National Healthcare Institute (The Netherlands). The following contexts for RWD use in REA of drugs were reviewed: initial reimbursement discussions, pharmacoeconomic analyses, and conditional reimbursement schemes. We identified 13 policy documents and 9 academic publications, and conducted 6 interviews. Results: Policies for RWD use in REA of drugs notably differed across contexts. Moreover, policies differed between HTA agencies. Such variations might discourage the use of RWD for HTA. Conclusions: To facilitate the use of RWD for HTA across Europe, more alignment of policies seems necessary. Recent articles and project proposals of the European network of HTA may provide a starting point to achieve this. Copyright (C) 2017, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc.

Purpose To assess the risk of gastrointestinal perforation, ulcers, or bleeding (PUB) associated with the use of conventional nonsteroidal anti‐inflammatory drugs (NSAIDs) with proton pump inhibitors (PPIs) and selective COX‐2 inhibitors, with or without PPIs compared with conventional NSAIDs. Methods A case–control study was performed within conventional NSAIDs and/or selective COX‐2 inhibitors users identified from the Dutch PHARMO Record Linkage System in the period 1998–2012. Cases were patients aged ≥18 years with a first hospital admission for PUB. For each case, up to four controls were matched for age and sex at the date a case was hospitalized (index date). Logistic regression analysis was used to calculate odds ratios (ORs). Results At the index date, 2634 cases and 5074 controls were current users of conventional NSAIDs or selective COX‐2 inhibitors. Compared with conventional NSAIDs, selective COX‐2 inhibitors with PPIs had the lowest risk of PUB (adjusted OR 0.51, 95% confidence interval [CI]: 0.35–0.73) followed by selective COX‐2 inhibitors (adjusted OR 0.66, 95%CI: 0.48–0.89) and conventional NSAIDs with PPIs (adjusted OR 0.79, 95%CI: 0.68–0.92). Compared with conventional NSAIDs, the risk of PUB was lower for those aged ≥75 years taking conventional NSAIDs with PPIs compared with younger patients (adjusted interaction OR 0.79, 95%CI: 0.64–0.99). However, those aged ≥75 years taking selective COX‐2 inhibitors, the risk was higher compared with younger patients (adjusted interaction OR 1.22, 95%CI: 1.01–1.47). Conclusions Selective COX‐2 inhibitors with PPIs, selective COX‐2 inhibitors, and conventional NSAIDs with PPIs were associated with lower risks of PUB compared with conventional NSAIDs. These effects were modified by age. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.

Prolongation of the QT interval can predispose to fatal ventricular arrhythmias. Differences in QT-labeling language can result in miscommunication and suboptimal risk mitigation. We systematically compared the phraseology used to communicate on QT-prolonging properties of 144 drugs newly approved (1st January 2006 to 1st June 2012) in the European Union (EU) and the United States (US), of which 66 mentioned the term 'QT' (two EU only, 28 US only, 36 both). The agreement between authorities about the message on QT prolongation (does not prolong, unclear, possibly prolongs, prolongs) was moderate (kappa 0.434). However, the agreement in expected clinical decisions based on the product labels was much higher (kappa 0.673). The US drug label tends to be more explicit, especially when it considers absence of QT effects. © 2014 Elsevier Ltd. All rights reserved.

BACKGROUND: Hypochlorhydric states are an important cause of iron deficiency (ID). Nevertheless, the association between therapy with proton pump inhibitors (PPIs) and ID has long been a subject of debate. This case-control study aimed to investigate the risk of ID associated with the use of PPIs using the UK Clinical Practice Research Datalink (CRPD) database. METHODS: Cases were patients aged 19 years or older with first-time diagnosis of ID between 2005 and 2015 (n = 26,806). The dates of first diagnosis of ID in cases defined the index dates. For each case, one control was matched by age, sex and general practice. A PPI "full" user (PFU) was defined as a subject who had received PPIs for a continuous duration of at least one year prior to the index date. A PPI "limited" users (PLU) was a subject who intermittently received PPI therapy. A PPI non-user (PNU) was a subject who received no PPIs prescriptions prior to the index date. The odds ratio of ID in PFU and PLU compared to PNU was estimated using conditional logistic regression. RESULTS: Among cases, 2,960 were PFU, 6,607 PLU and 17,239 PNU. Among controls, 1,091 were PFU, 5,058 PLU and 20,657 PNU. Adjusted odds ratio of ID in PFU and PLU compared to PNU was 3.60 (95%CI, [3.32 - 3.91]) and 1.51 (95% CI, [1.44 - 1.58]). Positive dose-response and time-response relationships were observed. CONCLUSIONS: Chronic PPI use increases the risk of ID. Physicians should consider this when balancing the risks and benefits of chronic PPI prescription. This article is protected by copyright. All rights reserved.

Background. In a recent randomized controlled trial (RCT) in obese adolescents, 18 month-treatment with metformin versus placebo was reported to lead to stabilisation of the BMI. This study aimed to compare the effect of metformin on BMI in obese adolescents in daily practice versus results obtained in an RCT.Methods. Obese adolescents treated off label with metformin in daily practice in an outpatient clinic with a follow-up of ≥18 months were identified. Anthropometric and biochemical data were collected at baseline and at 18 months. Patients treated with metformin for 18 months in an RCT were used for comparison. BMI was compared between the two groups.Results. Nineteen patients (median age 14.3 (interquartile range 11.7–15.7) years, BMI 31.3 (28.8–33.8) kg/m2) treated in daily practice were compared to 23 patients receiving metformin in the RCT (age 13.6 (12.6–15.3) years, BMI 29.8 (28.1–34.5) kg/m2). BMI change after 18 months was −0.36 (−2.10–1.58) versus +0.22 (−2.87–1.27) kg/m2for the two groups, respectively. In the multivariable model, BMI change was not statistically significantly different between the two groups (p=0.61).Conclusion. Treatment with metformin in obese adolescents in daily practice resulted in a comparable change in BMI as observed in an RCT. This trial is registered with ClinicalTrials.gov number:NCT01487993.

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.