Effects of European Society of Cardiology guidelines on medication profiles after hospitalization for heart failure in 22,476 Dutch patients: from 2001 until 2015.

Prescriber adherence to guideline-recommended medication in patients with heart failure (HF) in clinical practice is suboptimal. We analyzed how evolving guideline recommendations influenced medication profiles after a first HF hospitalization. We extracted medication profiles from the Dutch PHARMO Database Network for 22,476 patients with a diagnosis of HF at hospital discharge between 2001 and 2015. The percentage of patients prescribed the combination of a beta-blocker (BB) and an angiotensin-converting-enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB) increased from 24 to approximately 45% within this 15-year period. The percentage of patients who also used a mineralocorticoid-receptor antagonist (MRA) reached approximately 20%. The probability of being prescribed these combinations decreased with increasing age. As a consequence of the policy change in the ESC guideline 2001, the use of BB increased from less than 40% in 2001 to about 70% by 2015. The percentage of patients prescribed an ACEI and/or an ARB, an MRA, or a diuretic was about stable, at respectively 63%, 37%, and 82%. Although the 2012 ESC guideline also advised MRA in the New York Heart Association (NYHA) class II, there was no increase in MRA prescriptions. Compliance with the ESC guidelines varied for the individual recommendations. Remarkably, there was no significant increase in MRA prescriptions. At the same time, developments were demonstrated, which were not instigated by the guidelines, like the shift from ACEI to ARB. Although the exact HF classification of our patients was unknown, given a relatively stable case mix, our data provide insight into "real-world" pharmacological management.

Amiodarone Rifampicin Drug-Drug Interaction Management With Therapeutic Drug Monitoring.

The authors present a case of a 69-year-old man with arrhythmogenic right ventricular cardiomyopathy controlled with amiodarone and an infected orthopedic prosthesis requiring treatment with rifampicin. This combination involves a pharmacokinetic drug-drug interaction leading to subtherapeutic drug concentrations of amiodarone and its active metabolite. The long half-life of amiodarone and its active metabolite in combination with the late onset and offset of cytochrome P4503A (CYP3A4) induction by rifampicin makes this a challenging drug-drug interaction to cope with in clinical practice. Before, during, and after rifampicin treatment, the serum concentrations of amiodarone and its active metabolite were measured and the amiodarone dose was adjusted accordingly. The amiodarone dose required to maintain effective concentrations was 450% of the initial dose. The drug-drug interaction between amiodarone and rifampicin is relevant, both clinically and pharmacokinetically, and can be managed by dose adjustments of amiodarone based on serum concentrations.

Structured medication reviews in Parkinson's disease: pharmacists' views, experiences and needs - a qualitative study.

Background: Executing structured medication reviews (SMRs) in primary care to optimize drug treatment is considered standard care of community pharmacists in the Netherlands. Patients with Parkinson's disease (PD) often face complex drug regimens for their symptomatic treatment and might, therefore, benefit from an SMR. However, previously, no effect of an SMR on quality of life in PD was found. In trying to improve the case management of PD, it is interesting to understand if and to what extent SMRs in PD patients are of added value in the pharmacist's opinion and what are assumed facilitating and hindering factors. Objectives: To analyse the process of executing SMRs in PD patients from a community pharmacist's point of view. Design: A cross-sectional, qualitative study was performed, consisting of face-to-face semi-structured in-depth interviews. Methods: The interviews were conducted with community pharmacists who executed at least one SMR in PD, till data saturation was reached. Interviews were transcribed verbatim, coded and analysed thematically using an iterative approach. Results: Thirteen pharmacists were interviewed. SMRs in PD were considered of added value, especially regarding patient contact and bonding, individualized care and its possible effect in the future, although PD treatment is found already well monitored in secondary care. Major constraints were time, logistics and collaboration with medical specialists. Conclusion: Although community pharmacist-led SMRs are time-consuming and sometimes logistically challenging, they are of added value in primary care in general, and also in PD, of which treatment occurs mainly in secondary care. It emphasizes the pharmacist's role in PD treatment and might tackle future drug-related issues. Improvements concern multidisciplinary collaboration for optimized SMR execution and results.

Structured medication reviews in Parkinson's disease: pharmacists' views, experiences and needs Why is this research done? In Parkinson's disease (PD), drug therapy is still the most important treatment strategy. Due to disease progression, patients often face complicated medication regimens, polypharmacy, and potential drug-related problems. The execution of structured medication reviews (SMR) in primary care is considered standard care of community pharmacists in the Netherlands, aiming to optimise drug treatment. Although it might also affect clinical outcomes, we found no effect of an SMR in PD on quality of life in our previous study. In trying to improve case management of PD, we need to understand if and to what extent SMRs in PD patients are of added value in the pharmacist's opinion, and what are assumed facilitating and hindering factors. What did the researchers do? We conducted semi-structured interviews with 13 community pharmacists who recently executed ⩾1 SMR in PD. What did the researchers find? We found that SMRs in PD are considered of added value with regard to patient bonding and individualised care. By being known by the pharmacist, and vice versa, by knowing the patient's situation, future drug problems might be tackled earlier. However, executing SMRs comes with barriers, of which lack of time, logistic constraints and difficulties in cooperation with the medical specialist are the most important. What do these findings mean? Taking into account both the pharmacist's effort and additional costs when performing an SMR in the current setting, the valuable time of a pharmacist could potentially better be spent on more (cost-)effective interventions, or a structural solution should be sought for the experienced hindering factors. Since we do not doubt the importance of periodic medication optimization in complex diseases or high-risk patients, we have to focus on either improving the current setting of SMRs in PD, or searching for other strategies in which this can be achieved.

Discontinuation of infliximab treatment in patients with inflammatory bowel disease who retransitioned to originator and those who remained on biosimilar.

Background: Many patients with inflammatory bowel disease (IBD) have transitioned from an infliximab originator to a biosimilar. However, some patients retransition to the originator (i.e. stop biosimilar and reinitiate the originator). Whether this sign of potential unsatisfactory treatment response is specifically related to the infliximab biosimilar or the patient and/or the disease including patients' beliefs on the biosimilar is unclear. Objectives: We aimed to compare the risk of and reasons for infliximab discontinuation between retransitioned patients and those remaining on biosimilar. Design: Non-interventional, multicentre cohort study. Methods: IBD patients who transitioned from infliximab originator to biosimilar between January 2015 and September 2019 in two Dutch hospitals were eligible for this study. Retransitioned patients (retransitioning cohort) were matched with patients remaining on biosimilar (biosimilar remainder cohort). Reasons for discontinuation were categorised as the unwanted response (i.e. loss of effect or adverse events) or remission. Risk of unwanted discontinuation was compared using Cox proportional hazards models. Results: Patients in the retransitioning cohort (n = 44) were younger (median age 39.9 versus 44.0 years), more often female (65.9% versus 48.9%) and had shorter dosing intervals (median 48.5 versus 56.0 days) than in the biosimilar remainder cohort (n = 127). Infliximab discontinuation due to unwanted response was 22.7% in the retransitioning and 13.4% in the biosimilar remainder cohort, and due to remission was 2.3% and 9.4%, respectively. Retransitioned patients are at increased risk of discontinuing due to unwanted response compared with biosimilar remainder patients (adjusted HR 3.7, 95% CI: 1.0-13.9). Patients who retransitioned due to an increase in objective disease markers had higher discontinuation rates than patients who retransitioned due to symptoms only (66.7% versus 23.7%). Conclusion: Retransitioned patients are at increased risk of infliximab discontinuation due to unwanted response. Retransitioning appeared related to the patient and/or disease and not the product. Clinicians might switch patients opting for retransitioning to other treatment regimens.

Dopamine agonists and ischemic complications in Parkinson's disease: a nested case-control study.

BACKGROUND: It has been suggested that ergoline dopamine agonists can cause ischemic complications. The effect of dopamine agonists in general on the prevalence of ischemic events in patients with Parkinson's disease (PD) has not been studied. OBJECTIVE: Our aim was to investigate the association between the use of dopamine agonists and hospitalization due to ischemic events in patients with PD. METHODS: We performed a nested case-control study using the PHARMO Institute for Drug Outcome Research database. All patients issued at least one prescription for levodopa after the age of 55 years between 1994 and 2006 were initially identified. Cases were patients who were hospitalized for the first time after November 1997 for an ischemic event and were matched to as many as four controls. Exposure to dopamine agonists during the year preceding the index date was identified. RESULTS: The study population consisted of 542 cases and 2,155 controls. The mean effect of dopamine agonist use 1 year prior to the index date on ischemic events requiring hospitalization is shown with 95% probability in the 0.95-1.49 range. Stratified results according to the type of dopamine agonist showed no risk differences between ergoline and nonergoline agonists. CONCLUSIONS: This study does not support an association between dopamine agonist use and an increased risk of ischemic events requiring hospitalization.

Non-cardiovascular medication and readmission for heart failure: an observational cohort study.

Background Among heart failure (HF) patients, hospital readmissions are a major concern. The medication taken by a patient may provide information on comorbidities and conditions and may be used as an indicator to identify populations at an increased risk of HF readmission. Aim This study explored the use of non-cardiovascular medication at hospital discharge from the first HF admission in search of indicators of high risk of readmission for HF. Method The study included 22,476 HF patients from the Dutch PHARMO Database Network at their first HF hospitalization. The data was divided into training and validation sets. A Cox regression model with demographics, date of first HF hospital admission and non-cardiovascular medication present at discharge, adjusted for cardiovascular medication, was developed in the training set and subsequently implemented in the validation set. Results The study included 22,476 patients, mean age 76.7 years (range 18-104) and median follow-up time 2.5 years (range 0-15.7 years). During the study period 6,725 (29.9%) patients were readmitted for HF, with a median time-to-readmission of 7 months (range 0-14.3 years). Non-cardiovascular medication associated with a high risk of readmission for HF were identified as indicators of high risk, with no implied causal relationship. Patients prescribed antigout medications presented a 25% increased risk of readmission (HR 1.25, 95%CI 1.09-1.45, P = 0.002). Patients using insulin had an 18% higher risk of readmission versus patients not using insulin (HR 1.18, 95%CI 1.06-1.32, P = 0.002), but not versus patients treated with other blood-glucose-lowering drugs. No association between the risk of readmission and NSAIDs use was observed. Conclusion The results suggest that diabetes is responsible for the higher HF-readmission risk observed in patients prescribed insulin. The observed risk in users of antigout medication should be further investigated. The absence of an association with the use of NSAIDs should be interpreted with caution.

The Effect of a Structured Medication Review on Quality of Life in Parkinson's Disease.

BACKGROUND: Drug therapy is important for controlling symptoms in Parkinson's disease (PD). However, it often results in complex medication regimens and could easily lead to drug related problems (DRP), suboptimal adherence and reduced treatment efficacy. A structured medication review (SMR) could address these issues and optimize therapy, although little is known about clinical effects in PD patients. OBJECTIVE: To analyze whether an SMR improves quality of life (QoL) in PD. METHODS: In this multicenter randomized controlled trial, half of the 202 PD patients with polypharmacy received a community pharmacist-led SMR. The control group received usual care. Assessments at baseline, and after three and six months comprised six validated questionnaires. Primary outcome was PD specific QoL [(PDQ-39; range 0 (best QoL) - 100 (worst QoL)]. Secondary outcomes were disability score, non-motor symptoms, general health status, and personal care giver's QoL. Furthermore, DRPs, proposed interventions, and implemented modifications in medication schedules were analyzed. RESULTS: No improvement in QoL was seen six months after an SMR, with a non-significant treatment effect difference of 2.09 (-0.63;4.80) in favor of the control group. No differences were found in secondary outcomes. In total, 260 potential DRPs were identified (2.6 (±1.8) per patient), of which 62% led to drug therapy optimization. CONCLUSION: In the current setting, a community pharmacist-led SMR did not improve QoL in PD patients, nor improved other pre-specified outcomes.

Impact of malnourishment on the pharmacokinetics of acetaminophen and susceptibility to acetaminophen hepatotoxicity.

BACKGROUND: Acetaminophen hepatotoxicity is thought to be primarily caused by formation of the specific reactive metabolite N-acetyl-para-benzo-quinone imine (NAPQI). Malnourished individuals are at increased risk of acetaminophen-related hepatotoxicity. We report a case of low acetaminophen clearance in a severely underweight young woman, and elaborate on the possible effects of malnutrition on the total clearance of acetaminophen as well as on the separate contributions of the different metabolic pathways. CASE REPORT: An 18-year-old Caucasian woman weighing 43 kg with a history of eating disorder-related hospital admissions presented at the emergency department after having ingested 33 tablets of acetaminophen 500 mg two hours earlier. She then received intravenous N-acetylcysteine for 33 h. Nine hours after ingestion, the acetaminophen elimination half-life (t½) was estimated to be >100 h. DISCUSSION: While decreased total acetaminophen clearance (twofold) due to malnutrition has been reported in literature, the extremely low clearance in this specific patient cannot be explained. Malnourished individuals generally have reduced antioxidant reserves, coinciding with a shift in metabolic routes toward oxidative metabolism. This may result in increased formation of NAPQI and reduced neutralizing capacity, thereby increasing the risk of acetaminophen-induced hepatotoxicity. Evidence for this observation can be found in animal and to a lesser extent in human studies.

Switching TNFα inhibitors: Patterns and determinants.

The aim of this study was to assess switching patterns and determinants for switching in patients initiating TNFα inhibitor (TNFα-i) treatment. Patients were included who started TNFα-i treatment between July 1, 2012 and December 31, 2017, from three Dutch hospitals, and were diagnosed with rheumatic diseases (RD), inflammatory bowel disease (IBD), or psoriasis. Outcomes were switching, defined as initiating another biological; switching patterns including multiple switches until the end of follow-up; determinants for first switch, assessed using multivariate logistic regression. A total of 2228 patients were included (median age 43.3 years, 57% female), of which 52% (n = 1155) received TNFα-i for RD, 43% (n = 967) for IBD, and 5% (n = 106) for psoriasis. About 16.6% of RD patients, 14.5% of IBD patients, and 16.0% of psoriasis patients switched at least once, mainly to another TNFα-i. TNFα-i dose escalation (OR 13.78, 95% CI 1.40-135.0) and high-dose corticosteroids initiation (OR 3.62, 95% CI 1.10-12.15) were determinants for switching in RD patients. TNFα-i dose escalation (OR 8.22, 95% CI 3.76-17.93), immunomodulator initiation/dose escalation (OR 2.13, 95% CI 1.04-4.34), high-dose corticosteroids initiation (OR 6.91, 95% CI 2.81-17.01) and serum concentration measurement (OR 5.44, 95% CI 2.74-10.79) were determinants for switching in IBD patients. Switching biological treatment occurred in about one in six patients. RD patients with TNFα-i dose escalation and/or high-dose corticosteroids initiation were more likely to switch. IBD patients with TNFα-i or immunomodulator initiation/dose escalation, high-dose corticosteroids initiation or serum concentration measurement were more likely to switch. These findings might help clinicians anticipating switching in TNFα-i treatment.

The Impact of Non-dopaminergic Medication on Quality of Life in Parkinson's Disease.

BACKGROUND AND OBJECTIVES: Quality of life (QoL) in Parkinson's disease (PD) depends on multiple factors. Due to PD treatment and accompanying, age-related or independent comorbidities, pill burden is often high. The relation of QoL and pharmacotherapy for comorbidities in PD has not been widely studied. This study investigated if and to what extent non-dopaminergic drugs are related to QoL in PD. Second, the impact of demographics and non-motor symptoms were evaluated. A better understanding of the impact of different non-dopaminergic drugs and polypharmacy on QoL will have added value in selecting appropriate (medication) interventions. METHODS: In a cross-sectional analysis, medication prescription data of 209 PD patients were analyzed and grouped according to the Rx-Risk comorbidity index. QoL was measured using the PDQ-39 questionnaire. Non-motor symptoms were analyzed with the Non-Motor Symptoms questionnaire. Independent factors associated with a reduced QoL were identified with a multivariate linear regression analysis. RESULTS: Non-dopaminergic drugs, subdivided into Rx-Risk comorbidity categories, were not associated with reduced QoL, except for the use of anti-epileptic drugs. However, using more daily non-dopaminergic drugs was also negatively associated with QoL, as well as female sex, increased PD severity, and more non-motor symptoms. Contraindicated non-dopaminergic medication was barely prescribed (0.4%). CONCLUSION: Non-dopaminergic drugs are frequently prescribed, and higher numbers are associated with impaired QoL in PD. However, when divided in drug types, only anti-epileptic drugs were negatively associated with QoL. In these patients, physicians might improve QoL by further optimizing the condition it was prescribed for (e.g., pain or anxiety), or managing of side effects. TRIAL REGISTRATION: Netherlands Trial Register; NL4360.

Study protocol for a randomised controlled trial on the effect of local analgesia for pain relief after minimal invasive sacroiliac joint fusion: the ARTEMIS study.

INTRODUCTION: Chronic lower back pain is a common report in the general population. A dysfunctional sacroiliac joint (SIJ) is estimated to be responsible for one in five patients with lower back pain. Minimally invasive sacroiliac joint fusion (MISJF) is a surgical procedure to treat SIJ dysfunction. During the procedure, the SIJ is stabilised by implants inserted percutaneously under fluoroscopy guidance. Postoperatively, patients often report a lot of pain, which contributes to patients taking high doses of painkillers (opioids for example,) and preventing early mobilisation. In several orthopaedic procedures, intraoperative infiltration of the wound bed results in decreased consumption of analgesics, earlier mobilisation and shorter hospitalisation time. The aim of this study is to investigate the effectiveness of intraoperative SIJ infiltration with analgesia in reducing postoperative pain after MISJF. METHODS AND ANALYSIS: We will perform a two-centre, prospective, double-blind, randomised controlled trial to determine whether SIJ infiltration with 1.5-5 cc bupivacaine 0.50% is superior to 1.5-5 cc placebo (NaCl 0.9%) in reducing postoperative pain in patients after MISJF, and to determine whether bupivacaine significantly reduces opioid use in the direct postoperative period. Patients will be randomised with 1:1 allocation for either bupivacaine (intervention) or placebo SIJ infiltration. Postoperative pain will be measured by the Visual Analogue Scale pain score at entry and exit recovery, 2, 4, 6, 24 and 48 hours postoperatively. ETHICS AND DISSEMINATION: This is the first trial that investigates the effectiveness of intraoperative SIJ infiltration with bupivacaine 0.50% in reducing postoperative pain after MISJF. If intraoperative SIJ infiltration with bupivacaine 0.50% proves to be effective, this might have important clinical implications, such as postoperative analgesics (opioids for example,) consumption, earlier mobilisation and potentially shorter hospitalisation time. TRIAL REGISTRATION NUMBER: NL9151.

Does immediate smart feedback on therapy adherence and inhalation technique improve asthma control in children with uncontrolled asthma? A study protocol of the IMAGINE I study.

BACKGROUND: Many asthmatic children suffer from uncontrolled asthma with frequent exacerbations, despite an optimal treatment plan using inhalation medication. Studies have shown that therapy adherence and inhalation technique are often suboptimal in asthmatic children, but these have traditionally been hard to measure. A novel device functioning as an add-on to the inhaler has been developed to measure both aspects by recording vibration patterns during inhalation. This data can be converted to smart feedback and provided to patients immediately via a mobile application. The aim of this study is to improve asthma control in children between 6 and 18 years old by providing immediate smart feedback on the intake of inhalation medication. Asthma control will be measured by forced expiratory volume in 1 s, (Childhood) Asthma Control Test ((c-)ACT) score, and lung function variability and reversibility. METHODS: The study will be performed in Medisch Spectrum Twente (Enschede, The Netherlands). The goal is to include 68 uncontrolled moderate to severe asthmatic children between 6 and 18 years old who receive controller inhalation medication through the Nexthaler®, Ellipta®, or Spiromax®. The study consists of three phases. Phase 1 is observational and will last 4 weeks to observe the baseline adherence and inhalation technique as monitored by the add-on device. A randomised controlled trial lasting 6 weeks will be performed in phase 2. Patients in the intervention group will receive immediate smart feedback about the performed inhalations via a mobile application. In the control group, adherence and inhalation technique will be monitored, but patients will not receive feedback. In phase 3, also lasting 6 weeks, the feedback will be ceased for all children and revision of current therapy may occur, depending on the findings in phase 2. Asthma control can be assessed by means of spirometry (both at home and in the hospital) and (c-)ACT questionnaires. DISCUSSION: Immediate smart feedback may improve therapy adherence and inhalation technique, and thus asthma control in children and prevent unnecessary switches to targeted biologics. Performing this study in children is desired, since they are known to react differently to feedback and medication than adults. TRIAL REGISTRATION: Dutch Trial Register NL7705 . Registered on 29 April 2019.

Heart failure medication after a first hospital admission and risk of heart failure readmission, focus on beta-blockers and renin-angiotensin-aldosterone system medication: A retrospective cohort study in linked databases.

BACKGROUND: This study assessed the association between heart failure (HF) medication (angiotensin-converting-enzyme inhibitors (ACEI)/angiotensin-receptor blockers (ARB), beta-blockers (BB), mineralocorticoid-receptor antagonists (MRA) and diuretics) and HF readmissions in a real-world unselected group of patients after a first hospital admission for HF. Furthermore we analysed readmission rates for ACEI versus ARB and for carvedilol versus ß1-selective BB and we investigated the effect of HF medication in relation to time since discharge. METHODS AND FINDINGS: Medication at discharge was determined with dispensing data from the Dutch PHARMO Database Network including 22,476 patients with HF between 2001 and 2015. After adjustment for age, gender, number of medications and year of admission no associations were found for users versus non-users of ACEI/ARB (hazard ratio, HR = 1.01; 95%CI 0.96-1.06), BB (HR = 1.00; 95%CI 0.95-1.05) and readmissions. The risk of readmission for patients prescribed MRA (HR = 1.11; 95%CI 1.05-1.16) or diuretics (HR = 1.17; 95%CI 1.09-1.25) was higher than for non-users. The HR for ARB relative to ACEI was 1.04 (95%CI 0.97-1.12) and for carvedilol relative to ß1-selective BB 1.33 (95%CI 1.20-1.46). Post-hoc analyses showed a protective effect shortly after discharge for most medications. For example one month post discharge the HR for ACEI/ARB was 0.77 (95%CI 0.69-0.86). Although we did try to adjust for confounding by indication, probably residual confounding is still present. CONCLUSIONS: Patients who were prescribed carvedilol have a higher or at least a similar risk of HF readmission compared to ß1-selective BB. This study showed that all groups of HF medication -some more pronounced than others- were more effective immediately following discharge.

Clinical and pharmacogenetic determinants for the discontinuation of non-ergoline dopamine agonists in Parkinson's disease.

OBJECTIVE: To identify determinants for the discontinuation of non-ergoline dopamine agonist (DA) treatment in patients with Parkinson's disease (PD) and to identify genetic determinants in genes encoding dopamine receptor (DR)D2 and DRD3 in a exploratory analysis. METHODS: Patients included were first-time users of the non-ergoline DA ropinirole or pramipexole who had been diagnosed with PD before 2005. Treatment discontinuation was defined as a gap of 180 days or more between two refills of the DA. Non-genetic determinants for discontinuation were studied in the overall population, and genetic determinants [DRD2 141C Ins/Del, DRD2 (CA)n STR, DRD2 TaqIA, DRD3 MscI single nucleotide polymorphism (SNP) and DRD3 MspI SNP] were studied in a subgroup. Cox proportional hazard analysis was used to estimate the hazard ratios (HR) for the discontinuation of non-ergoline DA treatment. RESULTS: The study population comprised 90 patients. Apomorphine use was associated with non-ergoline DA discontinuation, although the apomorphine group consisted only of three patients [HR 6.26; 95% confidence interval (CI) 1.85­21.2]. Daily levodopa dosages between 500 and 1000 mg were positively associated with discontinuation (HR 2.31; 95% CI 1.08­4.93). Included in the exploratory pharmacogenetic analysis were 38 patients. The absence of a 15× DRD2 CA repeat allele was significantly related with a decreased discontinuation of non-ergoline treatment (HR 0.23; 95% CI 0.07­0.81). The DRD3 MspI polymorphism showed a non-significant allele dose effect, suggestive of a causal relationship. CONCLUSION: This study identified apomorphine use and levodopa dosages between 500 and 1000 mg as non-genetic and the 15× DRD2 CA repeat allele as genetic determinants for the discontinuation of non-ergoline DA treatment in patients with PD. More research is needed to replicate these findings.

Pharmacotherapy within a learning healthcare system: rationale for the Dutch Santeon Farmadatabase.

OBJECTIVES: The increasing number of available, often expensive, medicines asks for continuous assessment of rational prescribing. We aimed to develop a simple and robust data infrastructure in order to monitor hospital medicine utilisation in real time. METHODS: Within a collaboration (Santeon) of large teaching hospitals in the Netherlands, we set up a process for extraction, transformation, anonymisation and load of individual medicine prescription data and major clinical outcomes from different hospital information systems into a central database. Quarterly reports were constructed to monitor and validate the quality of the uploaded data. RESULTS: A central database has been developed that includes data from all patients from 2010 onwards and is refreshed on a weekly basis by an automated process. Beginning in 2017, the database holds data from almost 800 000 patients with prescriptions. All hospitals provide at least 18 mandatory data items per patient. Provided data include, among others, individual prescriptions, diagnosis data, and hospitalisation and survival data. The database is currently used to benchmark the level of biosimilar prescribing and to assess the impact of novel systemic treatments on survival rates in metastatic cancers. CONCLUSION: We showed that it is feasible for a group of hospitals to construct their own database that can serve as a tool to benchmark the positioning of medicines and to start with monitoring their impact on clinical outcomes.

Discontinuation of ropinirole and pramipexole in patients with Parkinson's disease: clinical practice versus clinical trials.

OBJECTIVE: To compare characteristics and incidence of discontinuation of Parkinson's disease (PD) patients starting ropinirole or pramipexole in clinical practice with data from randomised controlled clinical trials (RCTs). METHODS: Included in the retrospective clinical-practice cohort were first-time users of ropinirole or pramipexole diagnosed with PD before 2005. Baseline characteristics and incidence of discontinuation were compared between the clinical-practice cohort and RCTs. Treatment discontinuation was defined as more than 180 days between two refills of ropinirole or pramipexole. The incidence of discontinuation in RCTs was based on the reported rate of discontinuation for any cause. RESULTS: Included were 45 patients who started with ropinirole and 59 patients who started with pramipexole. Treatment was discontinued within 3 years in 51% (ropinirole) and 60% (pramipexole) of the patients. Ten RCTs with ropinirole and 12 with pramipexole were identified. Baseline characteristics did not differ between the clinical-practice cohort and RCTs. RCTs reported discontinuation rates comparable with those at the same timepoint in the clinical practice until 1 year of follow-up. CONCLUSION: This study shows that the overall incidence of discontinuation of ropinirole and pramipexole between the patients in our clinical-practice cohort and patients in the RCTs was comparable for the short term. However for the long term, discontinuation in practice is possibly higher.

Urine osmolality, cyclic AMP and aquaporin-2 in urine of patients under lithium treatment in response to water loading followed by vasopressin administration.

Lithium is the drug that is most frequently associated with acquired nephrogenic diabetes insipidus (NDI). The exact mechanism of lithium-induced NDI in man is unknown. The aim of the present study was to investigate the kidney response to minimal and maximal stimulation of the kidney urine concentrating mechanism by measuring urine osmolality, and urine levels of cAMP and AQP-2 in urine of patients under long-term lithium treatment. Twenty patients under long-term lithium treatment were included. The kidney urinary 3',5'-cyclic adenosine monophosphate (cyclic AMP), aquaporin-2 levels and urine osmolality were determined during a situation of minimal kidney urine concentrating activity (induced by water loading) and during a situation following maximal stimulation of kidney urine concentrating activity (induced by 1-desamino-8-D-arginine-vasopressin). Patients were classified as NDI, partial NDI and non-NDI based on maximal reached urine osmolality. The partial correlation (r) between urinary cyclic AMP levels (mol/l) and urine osmolality was 0.94 (P<0.001). No significant correlation was observed between urinary aquaporin-2 levels (mol/mol creatinine) and osmolality nor between urinary cyclic AMP and aquaporin-2 levels. The rise in urinary cyclic AMP but not aquaporin-2 levels upon 1-desamino-8-D-arginine-vasopressin administration after water loading significantly differed between the three categories, decreasing with increasing NDI category. In conclusion we found that in lithium-induced kidney urine concentrating deficit in man, the cyclic AMP generation in response to 1-desamino-8-D-arginine-vasopressin administration after water loading, is impaired. It remains to be elucidated whether principal cells, G-proteins or adenylate cyclase e.g. are the major targets for the mechanism underlying lithium-induced NDI in man.

A simple method for quantification of allopurinol and oxipurinol in human serum by high-performance liquid chromatography with UV-detection.

OBJECTIVES: Allopurinol is a uric acid lowering drug used in the treatment of gout and the prevention of tumor lysis syndrome. Allopurinol and its active metabolite oxipurinol inhibit xanthine oxidase, which forms uric acid from xanthine and hypoxanthine. Therapeutic drug monitoring is an important option for evaluation and optimization of allopurinol treatment in case of renal impairment, interaction with uricosuric drugs or to verify patient adherence. In this study we developed and validated a simple quantitative assay using reverse phased high-performance liquid chromatography (HPLC) with UV-detection as a method for quantification of allopurinol and oxipurinol in human serum in the presence of different frequently used drugs. METHODS: The HPLC-UV method uses a mobile phase consisting of sodium acetate (0.02 M; pH 4.5), at a flow rate of 1.0 mL/min. Allopurinol and oxipurinol are detected by UV-absorption at 254 nm with a retention time of 9.9 min for oxipurinol and 12.3 min for allopurinol. Aciclovir is used as internal standard. RESULTS: Validation showed for allopurinol lower and upper limits of quantification of 0.5 and 10mg/L and for oxipurinol 1 and 40 mg/L, respectively. The assay was linear over the concentration range of 0.5-10mg/L (allopurinol) and 1-40 mg/L (oxipurinol). Intra- and inter-day precision showed coefficients of variation <15% over the complete concentration range; accuracy was within 5% for allopurinol and oxipurinol. Endogenous purine-like compounds were separated from allopurinol, oxipurinol and aciclovir with a resolution factor >1.5. Exogenous purine-like compounds and co-medication frequently used by gout patients did not hinder the analysis due to the dichloromethane washing step or to low UV-absorpion at 253 nm. Serum levels of 66 patients prescribed allopurinol 300 mg/day were determined using this HPLC-UV method. Measured serum allopurinol and oxipurinol concentrations in clinical practice showed large variability with a range of <0.5-4.3 mg/L for allopurinol and <1.0-39.2 mg/L for oxipurinol, respectively. CONCLUSION: We developed an easy-to-operate and validated HPLC-UV method for the quantification of allopurinol and oxipurinol in human serum. This method was proven to be valid for samples of gout patients frequently using concomitant medications.

Decrease in Switches to 'Unsafe' Proton Pump Inhibitors After Communications About Interactions with Clopidogrel.

BACKGROUND: In 2009 and 2010 medicines regulatory agencies published official safety statements regarding the concomitant use of proton pump inhibitors and clopidogrel. We wanted to investigate a change in prescription behaviour in prevalent gastroprotective drug users (2008-2011). METHODS: Data on drug use were retrieved from the Out-patient Pharmacy Database of the PHARMO Database Network. We used interrupted time series analyses (ITS) to estimate the impact of each safety statement on the number of gastroprotective drug switches around the start of clopidogrel and during clopidogrel use. RESULTS: After the first statement (June 2009), significantly fewer patients switched from another proton pump inhibitor to (es)omeprazole (-14.9%; 95% CI -22.6 to -7.3) at the moment they started clopidogrel compared to the period prior to this statement. After the adjusted statement in February 2010, the switch percentage to (es)omeprazole decreased further (-4.5%; 95% CI -8.1 to -0.9). We observed a temporary increase in switches from proton pump inhibitors to histamine 2-receptor antagonists after the first statement; the decrease in the reverse switch was statistically significant (-23.0%; 95% CI -43.1 to -2.9). CONCLUSIONS: With ITS, we were able to demonstrate a decrease in switches from other proton pump inhibitors to (es)omeprazole and an increase of the reverse switch to almost 100%. We observed a partial and temporary switch to histamine 2-receptor antagonists. This effect of safety statements was shown for gastroprotective drug switches around the start of clopidogrel treatment.

Prescription behavior for gastroprotective drugs in new users as a result of communications regarding clopidogrel - proton pump inhibitor interaction.

Safety concerns of the concomitant use of clopidogrel and proton pump inhibitors (PPIs) were published in 2009 and 2010 by the medicines regulatory agencies, including a direct healthcare professional communication. We examined the association between various safety statements and prescription behavior for gastroprotective drugs in naïve patients in the Netherlands during the years 2008-2011. Data from the PHARMO Database Network were analyzed with interrupted time series analyses to estimate the impact of each communication on drug prescriptions. Dispensings were used as a proxy variable for prescription behavior. After the early communication in January 2009, 15.5% (95% CI 7.8, 23.4) more patients started concomitantly with (es)omeprazole and 13.8% (95% CI 6.5, 21.2) less with other PPIs. Directly after the first statement in June 2009, we found a steep increase in histamine 2-receptor antagonists (H2RA) peaking at 25%, placing those patients at risk for gastrointestinal events. This effect for H2RA faded away after a few months. In February 2010, when the official advice via an adjusted statement was to avoid (es)omeprazole, we found a decrease of 11.9% (95% CI 5.7, 18.2) for (es)omeprazole and an increase of +16.0% (95% CI 10.3, 21.7) for other PPIs. Still 22.6% (95% CI 19.5, 25.7) of patients started on (es)omeprazole in February 2010, placing them at risk for cardiovascular events. Advices of regulatory authorities were followed, however, reluctantly and not fully, probably partly because of the existing scientific doubt about the interaction.