Detectability of Medication Errors With a STOPP/START-Based Medication Review in Older People Prior to a Potentially Preventable Drug-Related Hospital Admission.

INTRODUCTION: Multimorbidity and polypharmacy are risk factors for drug-related hospital admissions (DRAs) in the ageing population. DRAs caused by medication errors (MEs) are considered potentially preventable. The STOPP/START criteria were developed to detect potential MEs in older people. OBJECTIVE: The aim of this study was to assess the detectability of MEs with a STOPP/START-based in-hospital medication review in older people with polypharmacy and multimorbidity prior to a potentially preventable DRA. METHODS: Hospitalised older patients (n = 963) with polypharmacy and multimorbidity from the intervention arm of the OPERAM trial received a STOPP/START-based in-hospital medication review by a pharmacotherapy team. Readmissions within 1 year after the in-hospital medication review were adjudicated for drug-relatedness. A retrospective assessment was performed to determine whether MEs identified at the first DRA were detectable during the in-hospital medication review. RESULTS: In total, 84 of 963 OPERAM intervention patients (8.7%) were readmitted with a potentially preventable DRA, of which 72 patients (n = 77 MEs) were eligible for analysis. About half (48%, n = 37/77) of the MEs were not present during the in-hospital medication review and therefore were not detectable at that time. The pharmacotherapy team recommended a change in medication regimen in 50% (n = 20/40) of present MEs, which corresponds to 26% (n = 20/77) of the total identified MEs at readmission. However, these recommendations were not implemented. CONCLUSION: MEs identified at readmission were not addressed by a prior single in-hospital medication review because either these MEs occurred after the medication review (~50%), or no recommendation was given during the medication review (~25%), or the recommendation was not implemented (~25%). Future research should focus on optimisation of the timing and frequency of medication review and the implementation of proposed medication recommendations. REGISTRATION: ClinicalTrials.gov identifier: NCT02986425. December 8, 2016. FUNDING: European Union HORIZON 2020, Swiss State Secretariat for Education, Research and Innovation (SERI), Swiss National Science Foundation (SNSF).

Performance of a trigger tool for detecting adverse drug reactions in patients with polypharmacy acutely admitted to the geriatric ward.

PURPOSE: Adverse drug reactions (ADRs) account for 10% of acute hospital admissions in older people, often under-recognised by physicians. The Dutch geriatric guideline recommends screening all acutely admitted older patients with polypharmacy with an ADR trigger tool comprising ten triggers and associated drugs frequently causing ADRs. This study investigated the performance of this tool and the recognition by usual care of ADRs detected with the tool. METHODS: A cross-sectional study was performed in patients ≥ 70 years with polypharmacy acutely admitted to the geriatric ward of the University Medical Centre Utrecht. Electronic health records (EHRs) were screened for trigger-drug combinations listed in the ADR trigger tool. Two independent appraisers assessed causal probability with the WHO-UMC algorithm and screened EHRs for recognition of ADRs by attending physicians. Performance of the tool was defined as the positive predictive value (PPV) for ADRs with a possible, probable or certain causal relation. RESULTS: In total, 941 trigger-drug combinations were present in 73% (n = 253/345) of the patients. The triggers fall, delirium, renal insufficiency and hyponatraemia covered 86% (n = 810/941) of all trigger-drug combinations. The overall PPV was 41.8% (n = 393/941), but the PPV for individual triggers was highly variable ranging from 0 to 100%. Usual care recognised the majority of ADRs (83.5%), increasing to 97.1% when restricted to possible and certain ADRs. CONCLUSION: The ADR trigger tool has predictive value; however, its implementation is unlikely to improve the detection of unrecognised ADRs in older patients acutely admitted to our geriatric ward. Future research is needed to investigate the tool's clinical value when applied to older patients acutely admitted to non-geriatric wards.

Performance of a trigger tool for detecting drug-related hospital admissions in older people: analysis from the OPERAM trial.

BACKGROUND: identifying drug-related hospital admissions (DRAs) in older people is difficult. A standardised chart review procedure has recently been developed. It includes an adjudication team (physician and pharmacist) screening using 26 triggers and then performing causality assessment to determine whether an adverse drug event (ADE) occurred (secondary to an adverse drug reaction, overuse, misuse or underuse) and whether the ADE contributed to hospital admission (DRA). OBJECTIVE: to assess the performance of those triggers in detecting DRA. DESIGN: retrospective study using data from the OPERAM (OPtimising thERapy to prevent Avoidable hospital admissions in Multimorbid older people) trial. SETTINGS: four European medical centres. SUBJECTS: multimorbid (≥ 3 chronic medical conditions) older (≥ 70 years) inpatients with polypharmacy (≥ 5 chronic medications) were enrolled in the OPERAM trial (N = 2,008) and followed for 12 months. We included patients with ≥1 adjudicated hospitalisation during the follow-up. METHODS: the positive predictive value (PPV; number of DRAs identified by trigger/number of triggers) was calculated for each trigger and for the tool as a whole. RESULTS: of 1,235 hospitalisations adjudicated for 832 patients, 716 (58%) had at least one trigger; an ADE was identified in 673 (54%) and 518 (42%) were adjudicated as DRAs. The overall PPV of the trigger tool for detecting DRAs was 0.66 [0.62-0.69]. CONCLUSIONS: this tool performs well for identifying DRAs in older people. Based on our results, a revised version of the tool was proposed but will require external validation before it can be incorporated into research and clinical practice.

Frequency and Acceptance of Clinical Decision Support System-Generated STOPP/START Signals for Hospitalised Older Patients with Polypharmacy and Multimorbidity.

BACKGROUND: The Screening Tool of Older Persons' Prescriptions (STOPP)/Screening Tool to Alert to Right Treatment (START) instrument is used to evaluate the appropriateness of medication in older people. STOPP/START criteria have been converted into software algorithms and implemented in a clinical decision support system (CDSS) to facilitate their use in clinical practice. OBJECTIVE: Our objective was to determine the frequency of CDSS-generated STOPP/START signals and their subsequent acceptance by a pharmacotherapy team in a hospital setting. DESIGN AND METHODS: Hospitalised older patients with polypharmacy and multimorbidity allocated to the intervention arm of the OPERAM (OPtimising thERapy to prevent Avoidable hospital admissions in the Multimorbid elderly) trial underwent a CDSS-assisted structured medication review in four European hospitals. We evaluated the frequency of CDSS-generated STOPP/START signals and the subsequent acceptance of these signals by a trained pharmacotherapy team consisting of a physician and pharmacist after evaluation of clinical applicability to the individual patient, prior to discussing pharmacotherapy optimisation recommendations with the patient and attending physicians. Multivariate linear regression analysis was used to investigate potential patient-related (e.g. age, number of co-morbidities and medications) and setting-related (e.g. ward type, country of inclusion) determinants for acceptance of STOPP and START signals. RESULTS: In 819/826 (99%) of the patients, at least one STOPP/START signal was generated using a set of 110 algorithms based on STOPP/START v2 criteria. Overall, 39% of the 5080 signals were accepted by the pharmacotherapy team. There was a high variability in the frequency and the subsequent acceptance of the individual STOPP/START criteria. The acceptance ranged from 2.5 to 75.8% for the top ten most frequently generated STOPP and START signals. The signal to stop a drug without a clinical indication was most frequently generated (28%), with more than half of the signals accepted (54%). No difference in mean acceptance of STOPP versus START signals was found. In multivariate analysis, most patient-related determinants did not predict acceptance, although the acceptance of START signals increased in patients with one or more hospital admissions (+ 7.9; 95% confidence interval [CI] 1.6-14.1) or one or more falls in the previous year (+ 7.1; 95% CI 0.7-13.4). A higher number of co-morbidities was associated with lower acceptance of STOPP (- 11.8%; 95% CI - 19.2 to - 4.5) and START (- 11.0%; 95% CI - 19.4 to - 2.6) signals for patients with more than nine and between seven and nine co-morbidities, respectively. For setting-related determinants, the acceptance differed significantly between the participating trial sites. Compared with Switzerland, the acceptance was higher in Ireland (STOPP: + 26.8%; 95% CI 16.8-36.7; START: + 31.1%; 95% CI 18.2-44.0) and in the Netherlands (STOPP: + 14.7%; 95% CI 7.8-21.7). Admission to a surgical ward was positively associated with acceptance of STOPP signals (+ 10.3%; 95% CI 3.8-16.8). CONCLUSION: The involvement of an expert team in translating population-based CDSS signals to individual patients is essential, as more than half of the signals for potential overuse, underuse, and misuse were not deemed clinically appropriate in a hospital setting. Patient-related potential determinants were poor predictors of acceptance. Future research investigating factors that affect patients' and physicians' agreement with medication changes recommended by expert teams may provide further insight for implementation in clinical practice. REGISTRATION: ClinicalTrials.gov Identifier: NCT02986425.

Prevalence of drug-drug interactions in older people before and after hospital admission: analysis from the OPERAM trial.

BACKGROUND: Drug-drug interactions (DDIs) are highly prevalent in older patients but little is known about prevalence of DDIs over time. Our main objective was to assess changes in the prevalence and characteristics of drug-drug interactions (DDIs) during a one-year period after hospital admission in older people, and associated risk factors. METHODS: We conducted a sub-study of the European OPERAM trial (OPtimising thERapy to prevent Avoidable hospital admissions in Multimorbid older people), which assessed the effects of a structured medication review (experimental arm) compared to usual care (control arm) on reducing drug-related hospital readmissions. All OPERAM patients (≥70 years, with multimorbidity and polypharmacy, hospitalized in four centers in Bern, Brussels, Cork and Utrecht between December 2016 and October 2018, followed over 1 year) who were alive at hospital discharge and had full medication data during the index hospitalization (at baseline i.e., enrolment at admission, and at discharge) were included. DDIs were assessed using an international consensus list of potentially clinically significant DDIs in older people. The point-prevalence of DDIs was evaluated at baseline, discharge, and at 2, 6 and 12 months after hospitalization. Logistic regression models were performed to assess independent variables associated with changes in DDIs 2 months after baseline. RESULTS: Of the 1950 patients (median age 79 years) included, 1045 (54%) had at least one potentially clinically significant DDI at baseline; point-prevalence rates were 58, 57, 56 and 57% at discharge, and 2, 6 and 12 months, respectively. The prevalence increased significantly from baseline to discharge (P < .001 [significant only in the control group]), then remained stable over time (P for trend .31). The five most common DDIs -all pharmacodynamic in nature- accounted for 80% of all DDIs and involved drugs that affect potassium concentrations, centrally-acting drugs and antithrombotics. At 2 months, DDIs had increased in 459 (27%) patients and decreased in 331 (19%). The main factor predictive of a change in the prevalence of DDIs was hyperpolypharmacy (≥10 medications). CONCLUSIONS: DDIs were very common; their prevalence increased during hospitalization and tended to remain stable thereafter. Medication review may help control this increase and minimize the risk of adverse drug events.

Optimizing Therapy to Prevent Avoidable Hospital Admissions in Multimorbid Older Adults (OPERAM): cluster randomised controlled trial.

OBJECTIVE: To examine the effect of optimising drug treatment on drug related hospital admissions in older adults with multimorbidity and polypharmacy admitted to hospital. DESIGN: Cluster randomised controlled trial. SETTING: 110 clusters of inpatient wards within university based hospitals in four European countries (Switzerland, Netherlands, Belgium, and Republic of Ireland) defined by attending hospital doctors. PARTICIPANTS: 2008 older adults (≥70 years) with multimorbidity (≥3 chronic conditions) and polypharmacy (≥5 drugs used long term). INTERVENTION: Clinical staff clusters were randomised to usual care or a structured pharmacotherapy optimisation intervention performed at the individual level jointly by a doctor and a pharmacist, with the support of a clinical decision software system deploying the screening tool of older person's prescriptions and screening tool to alert to the right treatment (STOPP/START) criteria to identify potentially inappropriate prescribing. MAIN OUTCOME MEASURE: Primary outcome was first drug related hospital admission within 12 months. RESULTS: 2008 older adults (median nine drugs) were randomised and enrolled in 54 intervention clusters (963 participants) and 56 control clusters (1045 participants) receiving usual care. In the intervention arm, 86.1% of participants (n=789) had inappropriate prescribing, with a mean of 2.75 (SD 2.24) STOPP/START recommendations for each participant. 62.2% (n=491) had ≥1 recommendation successfully implemented at two months, predominantly discontinuation of potentially inappropriate drugs. In the intervention group, 211 participants (21.9%) experienced a first drug related hospital admission compared with 234 (22.4%) in the control group. In the intention-to-treat analysis censored for death as competing event (n=375, 18.7%), the hazard ratio for first drug related hospital admission was 0.95 (95% confidence interval 0.77 to 1.17). In the per protocol analysis, the hazard ratio for a drug related hospital admission was 0.91 (0.69 to 1.19). The hazard ratio for first fall was 0.96 (0.79 to 1.15; 237 v 263 first falls) and for death was 0.90 (0.71 to 1.13; 172 v 203 deaths). CONCLUSIONS: Inappropriate prescribing was common in older adults with multimorbidity and polypharmacy admitted to hospital and was reduced through an intervention to optimise pharmacotherapy, but without effect on drug related hospital admissions. Additional efforts are needed to identify pharmacotherapy optimisation interventions that reduce inappropriate prescribing and improve patient outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02986425.

Intervention protocol: OPtimising thERapy to prevent avoidable hospital Admission in the Multi-morbid elderly (OPERAM): a structured medication review with support of a computerised decision support system.

BACKGROUND: Several approaches to medication optimisation by identifying drug-related problems in older people have been described. Although some interventions have shown reductions in drug-related problems (DRPs), evidence supporting the effectiveness of medication reviews on clinical and economic outcomes is lacking. Application of the STOPP/START (version 2) explicit screening tool for inappropriate prescribing has decreased inappropriate prescribing and significantly reduced adverse drug reactions (ADRs) and associated healthcare costs in older patients with multi-morbidity and polypharmacy. Therefore, application of STOPP/START criteria during a medication review is likely to be beneficial. Incorporation of explicit screening tools into clinical decision support systems (CDSS) has gained traction as a means to improve both quality and efficiency in the rather time-consuming medication review process. Although CDSS can generate more potential inappropriate medication recommendations, some of these have been shown to be less clinically relevant, resulting in alert fatigue. Moreover, explicit tools such as STOPP/START do not cover all relevant DRPs on an individual patient level. The OPERAM study aims to assess the impact of a structured drug review on the quality of pharmacotherapy in older people with multi-morbidity and polypharmacy. The aim of this paper is to describe the structured, multi-component intervention of the OPERAM trial and compare it with the approach in the comparator arm. METHOD: This paper describes a multi-component intervention, integrating interventions that have demonstrated effectiveness in defining DRPs. The intervention involves a structured history-taking of medication (SHiM), a medication review according to the systemic tool to reduce inappropriate prescribing (STRIP) method, assisted by a clinical decision support system (STRIP Assistant, STRIPA) with integrated STOPP/START criteria (version 2), followed by shared decision-making with both patient and attending physician. The developed method integrates patient input, patient data, involvement from other healthcare professionals and CDSS-assistance into one structured intervention. DISCUSSION: The clinical and economical effectiveness of this experimental intervention will be evaluated in a cohort of hospitalised, older patients with multi-morbidity and polypharmacy in the multicentre, randomized controlled OPERAM trial (OPtimising thERapy to prevent Avoidable hospital admissions in the Multi-morbid elderly), which will be completed in the last quarter of 2019. TRIAL REGISTRATION: Universal Trial Number: U1111-1181-9400 Clinicaltrials.gov: NCT02986425, Registered 08 December 2016. FOPH (Swiss national portal): SNCTP000002183. Netherlands Trial Register: NTR6012 (07-10-2016).

Evaluation of clarity of the STOPP/START criteria for clinical applicability in prescribing for older people: a quality appraisal study.

OBJECTIVES: Appropriate prescribing in older people continues to be challenging. Studies still report a high prevalence of inappropriate prescribing in older people. To reduce the problem of underprescribing and overprescribing in this population, explicit drug optimisation tools like Screening Tool of Older Persons' potentially inappropriate Prescriptions/Screening Tool to Alert to Right Treatment (STOPP/START) have been developed. The aim of this study was to evaluate the clinical applicability of STOPP/START criteria in daily patient care by assessing the clarity of singular criteria. DESIGN: Quality appraisal study. METHODS: For each of the 114 STOPP/START criteria V.2, elements describing the action (what/how to do), condition (when to do) and explanation (why to do) were identified. Next, the clarity of these three elements was quantified on a 7-point Likert scale using tools provided by the Appraisal of Guidelines for Research and Evaluation (AGREE) Consortium. PRIMARY AND SECONDARY OUTCOMES: The primary outcome measure was the clarity rating per element, categorised into high (>67.7%), moderate (33.3%-67.7%) or low (<33.3%). Secondary, factors that positively or negatively affected clarity most were identified. Additionally, the nature of the conditions was further classified into five descriptive components: disease, sign, symptom, laboratory finding and medication. RESULTS: STOPP recommendations had an average clarity rating of 64%, 60% and 69% for actions, conditions and explanations, respectively. The average clarity rating in START recommendations was 60% and 57% for actions and conditions, respectively. There were no statements present to substantiate the prescription of potential omissions for the 34 START criteria. CONCLUSIONS: Our results show that the clarity of the STOPP/START criteria can be improved. For future development of explicit drug optimisation tools, such as STOPP/START, our findings identified facilitators (high clarity) and barriers (low clarity) that can be used to improve the clarity of clinical practice guidelines on a language level and therefore enhance clinical applicability.

Prescribing medicines to older people-How to consider the impact of ageing on human organ and body functions.

Ageing is associated with several changes in human organs, which result in altered medication pharmacokinetics and pharmacodynamics. Ageing is also associated with changes in human body functions, such as impaired vision, hearing, swallowing, motor and cognitive functions, which can affect the adequate intake and administration of drugs. As a consequence, older people, and especially patients older than 75 years, are the main users of many drugs and they frequently use 5 drugs or more long-term (i.e. polypharmacy). All this increases the complexity of adequate drug intake, administration and adherence. However, there is a lack of evidence on the considerations that should be taken into account to ensure appropriate drug prescribing to older people. This review article summarizes the most clinically relevant changes in human organ and body functions and the consequential changes in pharmacokinetics and pharmacodynamics in older people, along with possible dosing consequences or alternatives for drugs frequently prescribed to this patient population. Recommendations are given on how ageing could be considered in clinical drug development, drug authorization and appropriate prescribing.

The effect of providing prescribing recommendations on appropriate prescribing: A cluster-randomized controlled trial in older adults in a preoperative setting.

AIMS: The Systematic Tool to Reduce Inappropriate Prescribing is a method to assess patient's medication and has been incorporated into a clinical decision support system: STRIP Assistant. Our aim was to evaluate the effect of recommendations generated using STRIP Assistant on appropriate prescribing and mortality in a preoperative setting. METHODS: This cluster-randomized controlled trial was carried out at the preoperative geriatric outpatient clinic. Residents who performed a comprehensive geriatric assessment were randomized to the control group and intervention group in a 1:1 ratio. Visiting patients aged 70 years or older on 5 or more medications were included. INTERVENTION: prescribing recommendations were generated by a physician using STRIP Assistant and given to the resident. Control group residents performed a medication review according to usual care. PRIMARY OUTCOME: number of medication changes made because of potential prescribing omissions (PPOs), potentially inappropriate medications (PIMs), and suboptimal dosages according to the prescribing recommendations. Secondary outcome: 3-month postoperative mortality. RESULTS: 65 intervention and 59 control patients were included, attended by 34 residents. Significantly more medication changes because of PPOs and PIMs were made in the intervention group than in the control group (PPOs 26.2% vs 3.4%, odds ratio 0.04 [95% confidence interval 0.003-0.46] P < .05; PIMS 46.2% vs 15.3% odds ratio 0.14 [95% confidence interval 0.07-0.57] P < .005). There were no differences in dose adjustments or in postoperative mortality. CONCLUSION: Prescribing recommendations generated with the help of STRIP Assistant improved appropriate prescribing in a preoperative geriatric outpatient clinic but did not affect postoperative mortality.

Age as a determinant of instability of serum lithium concentrations.

BACKGROUND: Lithium is used both in bipolar disorder and as augmentation in treatment-resistant unipolar depression. Long-term treatment is often indicated. Pharmacokinetic and pharmacodynamic changes in older age, as well as increasing comorbidities and polypharmacy, could result in instability of serum lithium concentrations. In this study, several parameters, considered proxy for instability, were compared between age groups. These parameters were derived from studies involving oral anticoagulants. METHODS: A retrospective study (1995-2004) was conducted using serum lithium concentrations from the laboratories of 3 hospitals in the Netherlands; 759 patients treated with lithium, 40 years or older, with at least 2 years' follow-up were identified. They were divided into 4 age groups: 40-49, 50-59, 60-69, and 70+ years; the youngest group was used as a reference group. The variance growth rate and percentage of time below, in, and above treatment range are all proxies for instability. They were analyzed between the age categories. RESULTS: There was no significant difference for these variables between the reference group and the older age groups. In a subgroup of 454 patients, the parameters considered as proxy for instability during titration, number of days and number of serum lithium concentration measurements during titration, were evaluated; no significant difference was found between the age groups. In a small group of 117 patients, titration and maintenance treatment for at least 2 years could be analyzed separately. Also in this group, there was no difference between the age groups. CONCLUSIONS: Age is not a determinant of serum lithium concentration instability. Therefore, age is not a reason to not initiate or discontinue lithium therapy.

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.

Pancreatitis, complicated by a pancreatic pseudocyst associated with the use of valproic acid.

A 12-year-old boy developed pancreatitis, complicated by a pancreatic pseudocyst, as an adverse reaction to valproic acid (VPA) treatment for epilepsy. Pancreatitis subsided within three weeks after discontinuation of VPA. The pancreatic pseudocyst was managed without surgery and resolved spontaneously in four weeks. Valproic acid was concluded to be the most probable cause, since no other explanation was found. According to the literature VPA is a rare but known cause of pancreatitis. A computer-assisted literature search revealed seven previously reported cases of VPA-induced pancreatitis complicated by a pancreatic pseudocyst. Six of these patients were under 20 years of age. Four patients were treated conservatively; three needed cystostomy or external drainage. All patients recovered. Patients using VPA, especially children, presenting with acute abdominal pain should be suspected of valproic acid-induced pancreatitis. If VPA induced pancreatitis is complicated by a pseudocyst, conservative treatment should be the first line of treatment.