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Purpose STOPP/START is a physiological systems-based explicit set of criteria that attempts to define the clinically important prescribing problems relating to potentially inappropriate medications (PIMs–STOPP criteria) and potential prescribing omissions (PPOs–START criteria). The previous two versions of STOPP/START criteria were published in 2008 and 2015. The present study describes the revised and updated third version of the criteria. Methods A detailed system-by-system review of the published literature from April 2014 to March 2022 was undertaken with the aim of including clinically important new explicit PIM and PPO criteria and removing any criteria considered to be no longer correct or outdated. A panel of 11 academic physicians with recognized expertise in geriatric pharmacotherapy from 8 European countries participated in a Delphi panel with the task of validating the draft criteria. The panel was presented with the draft new criteria using the SurveyMonkey® on-line platform in which panelists were asked to indicate their level of agreement on a five-point Likert scale. Results Two hundred and four evidence-based draft criteria (one hundred and forty-five STOPP criteria, fifty-nine START criteria) were presented to panelists for assessment using the Delphi validation method. Over the course of four rounds of Delphi validation, the panel achieved consensus on 133 STOPP criteria and 57 START criteria, i.e., 190 STOPP/START criteria in total representing a 66.7% increase in the number of criteria compared to STOPP/START version 2 published in 2015. Conclusion A fully revised and updated version of STOPP/START criteria has been validated by a European expert panel using the Delphi consensus process.

Background Diabetes overtreatment is a frequent and severe issue in multimorbid older patients with type 2 diabetes (T2D). Objective This study aimed at assessing the association between diabetes overtreatment and 1-year functional decline, hospitalisation and mortality in older inpatients with multimorbidity and polypharmacy. Methods Ancillary study of the European multicentre OPERAM project on multimorbid patients aged ≥70 years with T2D and glucose-lowering treatment (GLT). Diabetes overtreatment was defined according to the 2019 Endocrine Society guideline using HbA1c target range individualised according to the patient’s overall health status and the use of GLT with a high risk of hypoglycaemia. Multivariable regressions were used to assess the association between diabetes overtreatment and the three outcomes. Results Among the 490 patients with T2D on GLT (median age: 78 years; 38% female), 168 (34.3%) had diabetes overtreatment. In patients with diabetes overtreatment as compared with those not overtreated, there was no difference in functional decline (29.3% vs 38.0%, P = 0.088) nor hospitalisation rates (107.3 vs 125.8/100 p-y, P = 0.115) but there was a higher mortality rate (32.8 vs 21.4/100 p-y, P = 0.033). In multivariable analyses, diabetes overtreatment was not associated with functional decline nor hospitalisation (hazard ratio, HR [95%CI]: 0.80 [0.63; 1.02]) but was associated with a higher mortality rate (HR [95%CI]: 1.64 [1.06; 2.52]). Conclusions Diabetes overtreatment was associated with a higher mortality rate but not with hospitalisation or functional decline. Interventional studies should be undertaken to test the effect of de-intensifying GLT on clinical outcomes in overtreated patients.

BackgroundA patient-centred approach to medicines optimisation is considered essential. The OPtimising thERapy to prevent Avoidable hospital admissions in Multimorbid older people (OPERAM) trial evaluated the effectiveness of medication review with shared decision-making (SDM) in older people with multimorbidity. Beyond evaluating the clinical effectiveness, exploring the patient experience facilitates a better understanding of contextual factors and mechanisms affecting medication review effectiveness.ObjectiveTo explore experiences of hospital-initiated medication changes in older people with multimorbidity.MethodsWe conducted a multicentre mixed-methods study, embedded in the OPERAM trial, combining semi-structured interviews and the Beliefs about Medicines Questionnaire (BMQ) with a purposive sample of 48 patients (70–94 years) from four European countries. Interviews were analysed using the Framework approach. Trial implementation data on SDM were collected and the 9-item SDM questionnaire was conducted with 17 clinicians.ResultsPatients generally displayed positive attitudes towards medication review, yet emphasised the importance of long-term, trusting relationships such as with their general practitioners for medication review. Many patients reported a lack of information and communication about medication changes and predominantly experienced paternalistic decision-making. Patients’ beliefs that ‘doctors know best’, ‘blind trust’, having limited opportunities for questions, use of jargon terms by clinicians, ‘feeling too ill’, dismissive clinicians, etc highlight the powerlessness some patients felt during hospitalisation, all representing barriers to SDM. Conversely, involvement of companions, health literacy, empathetic and trusting patient-doctor relationships, facilitated SDM. Paradoxical to patients’ experiential accounts, clinicians reported high levels of SDM. The BMQ showed that most patients had high necessity and low concern beliefs about medicines. Beliefs about medicines, experiencing benefits or harms from medication changes, illness perception, trust and balancing advice between different healthcare professionals all affected acceptance of medication changes.ConclusionTo meet patients’ needs, future medicines optimisation interventions should enhance information exchange, better prepare patients and clinicians for partnership in care and foster collaborative medication reviews across care settings.

BACKGROUND Identifying patients at high risk of drug-related hospital admission (DRA) may help to efficiently target preventive interventions. We developed a score to predict DRAs in older patients with multimorbidity and polypharmacy. METHODS We used participants from the multicenter European OPERAM trial ("Optimising PharmacothERapy in the Mutlimorbid Elderly"). We assessed the association between easily identifiable predictors and 1-year DRAs by univariable logistic regression. Variables with p-value3 points had a 40.4% predicted and 38.9% observed risk of DRA. The scaled Brier score was 0.05. Calibration showed an adequate match between predicted and observed proportions. CONCLUSION Comorbidities related to drug metabolism, specific medications, non-elective admission, and a history of hospitalization, were associated with a higher risk of DRA. Awareness of these associations and the score we developed may help identify patients most likely to benefit from preventive interventions.

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

No abstract available

BACKGROUND Estimating life expectancy of older adults informs whether to pursue future investigation and therapy. Several models to predict mortality have been developed but often require data not immediately available during routine clinical care. The HOSPITAL score and the LACE index were previously validated to predict 30-day readmissions but may also help to assess mortality risk. We assessed their performance to predict 1-year and 30-day mortality in hospitalized older multimorbid patients with polypharmacy. METHODS We calculated the HOSPITAL score and LACE index in patients from the OPERAM (OPtimising thERapy to prevent Avoidable hospital admissions in the Multimorbid elderly) trial (patients aged �����70 years with multimorbidity and polypharmacy, admitted to hospital across four European countries in 2016-2018). Our primary and secondary outcomes were 1-year and 30-day mortality. We assessed the overall accuracy (scaled Brier score, the lower the better), calibration (predicted/observed proportions), and discrimination (C-statistic) of the models. RESULTS Within 1��year, 375/1879 (20.0%) patients had��died, including 94 deaths within 30 days. The overall accuracy was good and similar for both models (scaled Brier score 0.01-0.08). The C-statistics were identical for both models (0.69 for 1-year mortality, p��=��0.81; 0.66 for 30-day mortality, p��=��0.94). Calibration showed well-matching predicted/observed proportions. CONCLUSION The HOSPITAL score and LACE index showed similar performance to predict 1-year and 30-day mortality in older multimorbid patients with polypharmacy. Their overall accuracy was good, their discrimination low to moderate, and the calibration good. These simple tools may help predict older multimorbid patients' mortality after hospitalization, which may inform post-hospitalization intensity of care.

Purpose Older adults at the emergency department (ED) with polypharmacy, comorbidity, and frailty are at risk of adverse health outcomes. We investigated the association of polypharmacy with adverse health outcomes, in relation to comorbidity and frailty. Methods This is a prospective cohort study in ED patients ≥ 70 years. Non-polypharmacy was defined as 0–4 medications, polypharmacy 5–9 and excessive polypharmacy ≥ 10. Comorbidity was classified by the Charlson comorbidity index (CCI). Frailty was defined by the Identification of Seniors At Risk—Hospitalized Patients (ISAR-HP) score. The primary outcome was 3-month mortality. Secondary outcomes were readmission to an ED/hospital ward and a self-reported fall Results 881 patients were included. 43% had polypharmacy and 18% had excessive polypharmacy. After 3 months, 9% died, 30% were readmitted, and 21% reported a fall. Compared with non-polypharmacy, the odds ratio (OR) for mortality ranged from 2.62 (95% CI 1.39–4.93) in patients with polypharmacy to 3.92 (95% CI 1.95–7.90) in excessive polypharmacy. The OR weakened after adjustment for comorbidity: 1.80 (95% CI 0.92–3.52) and 2.32 (95% CI 1.10–4.90). After adjusting for frailty, the OR weakened to 2.10 (95% CI 1.10–4.00) and OR 2.40 (95% CI 1.15–5.02). No significant association was found for readmission or self-reported fall. Conclusions Polypharmacy is common in older patients at the ED. Polypharmacy, and especially excessive polypharmacy, is associated with an increased risk of mortality. The observed association is complex given the confounding effect of comorbidity and frailty.

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.

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

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

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 .

Background Older adults with chronic conditions are at high risk of complications from influenza and pneumococcal infections. Evidence about factors associated with influenza and pneumococcal vaccination among older multimorbid persons in Europe is limited. The aim of this study was to investigate the prevalence and determinants of these vaccinations in this population. Methods Multimorbid patients aged ≥70 years with polypharmacy were enrolled in 4 European centers in Switzerland, Belgium, the Netherlands, and Ireland. Data on vaccinations, demographics, health care contacts, and comorbidities were obtained from self-report, general practitioners and medical records. The association of comorbidities or medical contacts with vaccination status was assessed using multivariable adjusted log-binomial regression models. Results Among 1956 participants with available influenza vaccination data (median age 79 years, 45% women), 1314 (67%) received an influenza vaccination within the last year. Of 1400 patients with available pneumococcal vaccination data (median age 79 years, 46% women), prevalence of pneumococcal vaccination was 21% (n = 291). The prevalence of vaccination remained low in high-risk populations with chronic respiratory disease (34%) or diabetes (24%), but increased with an increasing number of outpatient medical contacts. Chronic respiratory disease was independently associated with the receipt of both influenza and pneumococcal vaccinations (prevalence ratio [PR] 1.09, 95% confidence interval [CI] 1.03–1.16; and PR 2.03, 95%CI 1.22–3.40, respectively), as was diabetes (PR 1.06, 95%CI 1.03–1.08; PR 1.24, 95%CI 1.16–1.34, respectively). An independent association was found between number of general practitioner visits and higher prevalence of pneumococcal vaccination (p for linear trend Conclusion Uptake of influenza and particularly of pneumococcal vaccination in this population of European multimorbid older inpatients remains insufficient and is determined by comorbidities and number and type of health care contacts, especially outpatient medical visits. Hospitalization may be an opportunity to promote vaccination, particularly targeting patients with few outpatient physician contacts.

Objective: To compare the effectiveness of single, multiple, and multifactorial interventions to prevent falls and fall-related fractures in community-dwelling older persons. Methods: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were systematically searched for randomized controlled trials (RCTs) evaluating the effectiveness of fall prevention interventions in communitydwelling adults aged ≥65 years, from inception until February 27, 2019. Two large RCTs (published in 2020 after the search closed) were included in post hoc analyses. Pairwise meta-analysis and network meta-analysis (NMA) were conducted. Results: NMA including 192 studies revealed that the following single interventions, compared with usual care, were associated with reductions in number of fallers: exercise (risk ratio [RR] 0.83; 95% confidence interval [CI] 0.77–0.89) and quality improvement strategies (e.g., patient education) (RR 0.90; 95% CI 0.83–0.98). Exercise as a single intervention was associated with a reduction in falls rate (RR 0.79; 95% CI 0.73–0.86). Common components of multiple interventions significantly associated with a reduction in number of fallers and falls rate were exercise, assistive technology, environmental assessment and modifications, quality improvement strategies, and basic falls risk assessment (e.g., medication review). Multifactorial interventions were associated with a reduction in falls rate (RR 0.87; 95% CI 0.80– 0.95), but not with a reduction in number of fallers (RR 0.95; 95% CI 0.89– 1.01). The following single interventions, compared with usual care, were associated with reductions in number of fall-related fractures: basic falls risk assessment (RR 0.60; 95% CI 0.39–0.94) and exercise (RR 0.62; 95% CI 0.42–0.90). Conclusions: In keeping with Tricco et al. (2017), several single and multiple fall prevention interventions are associated with fewer falls. In addition to Tricco, we observe a benefit at the NMA-level of some single interventions on preventing fall-related fractures.

We would like to thank Chen et al. for their comments on our recently published paper in Ageing Research Reviews (Veronese et al., 2021). In this reply we would like to answer to the points raised in their letter. Regarding the first question, we decided to run our search only in PubMed/Medline and ClinicalTrials.gov since the phase II-III randomized controlled trials of SARS-CoV 2 vaccines, considering the urgency for interventions to ameliorate the pandemic situation, received a great deal of interest. Therefore, they were usually published in high impact factor journals, reported in PubMed, and their protocols were usually reported in clinicaltrials.gov. However, following the suggestion of Chen et al., we did run a similar search in Web of Science (n = 150 articles) and Embase (n = 121 articles), without finding any possible eligible paper. We also searched, as suggested, the WHO ICTRP registry, which includes also the Chinese clinical trial registry, finding 36 ongoing trials, with two eligible out of them (https://trialsearch.who.int/Trial2.aspx? TrialID=ISRCTN79815558; https://trialsearch.who.int/Trial2.aspx? TrialID=RPCEC00000354). However, since both trials are still undergoing, it is not possible to know which percentage of older people will be eventually enrolled, therefore there is no need to modify what was already reported in our systematic review. With regard to the concern related to the language limitation, it should be pointed out that, among the completed trials, four out of ten were performed in China, but still they were published in an English language journal (Xia et al., 2020, 2021; Zhang et al., 2021; Zhu et al., 2020). Furthermore, we added the keywords suggested in the second point of the comments to our article: in this case, limiting the search to the 01st May 2021 as done in our systematic review, we found 547 possible eligible papers, but again, no new work was eligible for our analyses. Even if we recognize that adding these specific keywords might increase sensitivity of the search, they are probably of poor specificity in finding out papers that did not use randomized clinical trial as filter, particularly considering that practically all the papers reporting phase II-III trials on vaccination were published in widely known scientific journals. We also appreciate the comments regarding risk of bias and assessment of the quality of the study, which are a mandatory step in a systematic review. However, we would like to point out that the aim of our systematic review was not to investigate the efficacy/safety of COVID-19 vaccination in older people, but to highlight that older people were usually excluded from these studies. Therefore, this evaluation was not necessary, as we did not want to evaluate the quality of the results provided by the studies, but we aimed only at verifying the inclusion of older people. Finally, we are also grateful for the comments regarding the registration of the protocol and the statistical analysis. Regarding the first point, we agree that pre-publishing the protocol is an essential step in publishing a paper, but at the same time we also believe that the protocol structure is so simple in this case (we practically only extracted data regarding age range, asking to the corresponding authors further information when needed) that pre-publishing of the protocol would have not changed anything in the final results. However, we enclose to this letter as supplementary material the protocol. Moreover, the statistical analyses were so elementary that creating a specific paragraph would not represent an added value and we believe that keeping them in the outcomes section is enough for providing the necessary information to the readers to completely understand our work. In conclusion, we would like to thank Chen et al. for their comments that allowed us to confirm the methodological strengths of our paper. Indeed, as reported in this reply, addressing the points raised did not significantly change our results indicating that our work, even if simple, is correct and the conclusions are sound.

(N = 351) 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 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.

Background Healthcare professionals are often reluctant to deprescribe fall-risk-increasing drugs (FRIDs). Lack of knowledge and skills form a significant barrier and furthermore, there is no consensus on which medications are considered as FRIDs despite several systematic reviews. To support clinicians in the management of FRIDs and to facilitate the deprescribing process, STOPPFall (Screening Tool of Older Persons Prescriptions in older adults with high fall risk) and a deprescribing tool were developed by a European expert group. Methods STOPPFall was created by two facilitators based on evidence from recent meta-analyses and national fall prevention guidelines in Europe. Twenty-four panellists chose their level of agreement on a Likert scale with the items in the STOPPFall in three Delphi panel rounds. A threshold of 70% was selected for consensus a priori. The panellists were asked whether some agents are more fall-risk-increasing than others within the same pharmacological class. In an additional questionnaire, panellists were asked in which cases deprescribing of FRIDs should be considered and how it should be performed. Results The panellists agreed on 14 medication classes to be included in the STOPPFall. They were mostly psychotropic medications. The panellists indicated 18 differences between pharmacological subclasses with regard to fall-risk-increasing properties. Practical deprescribing guidance was developed for STOPPFall medication classes. Conclusion STOPPFall was created using an expert Delphi consensus process and combined with a practical deprescribing tool designed to optimise medication review. The effectiveness of these tools in falls prevention should be further evaluated in intervention studies.

AIMS Deprescribing interventions safely and effectively optimise medication use in older people. However, questions remain about which componentsof interventions are key to effectively reduce inappropriate medication use. This systematic review examines the behaviour change techniques (BCTs) of deprescribing interventions and summarises intervention effectiveness on medication use and inappropriate prescribing. METHODS MEDLINE, EMBASE, Web of Science and Academic Search Complete and grey literature were searched for relevant literature. Randomised controlled trials (RCTs) were included if they reported on interventions in people aged ≥65 years. The BCT taxonomy was used to identify BCTs frequently observed in deprescribing interventions. Effectiveness of interventions on inappropriate medication use was summarised in meta-analyses. Medication appropriateness was assessed in according to STOPP criteria, Beers' criteria and national or local guidelines Between study heterogeneity was evaluated by I-squared and Chi-squared statistics. Risk of bias was assessed using the Cochrane Collaboration Tool for randomised controlled studies. RESULTS Of the 1561 records identified, 25 studies were included in the review. Deprescribing interventions were effective in reducing number of drugs and inappropriate prescribing, but a large heterogeneity in effects was observed. BCT clusters including goals and planning; social support; shaping knowledge; natural consequences; comparison of behaviour; comparison of outcomes; regulation; antecedents; and identity had a positive effect on the effectiveness of interventions. CONCLUSIONS In general, deprescribing interventions effectively reduce medication use and inappropriate prescribing in older people. Successful deprescribing is facilitated by the combination of BCTs involving a range of intervention components.

During the COVID-19 pandemic older subjects have been disproportionately affected by the disease. Vaccination is a fundamental intervention to prevent the negative consequences of COVID-19, but it is not known if the needs and vulnerabilities of older people are adequately addressed by their inclusion in randomized clinical trials (RCTs) evaluating the efficacy of vaccines for COVID-19. Given this background, we aimed to evaluate if current and ongoing phase II-III RCTs evaluating the efficacy of COVID-19 vaccines included a representative sample of older people. A systematic literature search in PubMed and Clinicaltrials.gov was performed until May 01st, 2021. Among 474 abstracts initially retrieved, 20 RCTs (ten already published, ten ongoing) were included. In the ten studies already published, the mean age of participants was 45.2 ± 11.9 years and only 9.83% of the participants were more than 65 years, 1.66% more than 75 years and less than 1% (0.55%) more than 85 years. In the ten ongoing RCTs, many of the studies aimed at including participants older than 18 years, with one study including participants between 18 and 84 years, and two between 21 and 100 years. In conclusion, our systematic review demonstrates that in published and ongoing phase II-III randomized clinical trials evaluating the efficacy of COVID-19 vaccines only a tiny fraction of the most vulnerable group of older people was included, although they clearly were the first population that had to be vaccinated. © 2021 Elsevier B.V.

Jean-Baptiste Beuscart,1 Olivia Dalleur,1 Benoit Boland,2 Stefanie Thevelin,1 Wilma Knol,3 Shane Cullinan,4 Claudio Schneider,5 Denis O’Mahony,6 Nicolas Rodondi,4,7 Anne Spinewine1,8 1Université catholique de Louvain, Louvain Drug Research Institute, Clinical Pharmacy Research Group, Brussels, Belgium; 2Geriatric Medicine, Cliniques universitaires Saint-Luc, Brussels, Université catholique de Louvain, Belgium; 3Department of Geriatric Medicine and Expertise Centre Pharmacotherapy in Old Persons (EPHOR), University Medical Centre Utrecht, Netherlands; 4School of Pharmacy, Royal College of Surgeons in Ireland, Dublin, Ireland; 5Department of General Internal Medicine, Bern University Hospital, Bern, Switzerland; 6Department of Medicine (Geriatrics), University College Cork, Cork, Ireland; 7Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland; 8Université catholique de Louvain, CHU UCL Namur, Pharmacy Department, Yvoir, Belgium Background: Medication review has been advocated to address the challenge of polypharmacy in older patients, yet there is no consensus on how best to evaluate its efficacy. Heterogeneity of outcomes reported in clinical trials can hinder the comparison of clinical trial findings in systematic reviews. Moreover, the outcomes that matter most to older patients might be under-reported or disregarded altogether. A core outcome set can address this issue as it defines a minimum set of outcomes that should be reported in all clinical trials in any particular field of research. As part of the European Commission-funded project, called OPtimising thERapy to prevent Avoidable hospital admissions in the Multimorbid elderly, this paper describes the methods used to develop a core outcome set for clinical trials of medication review in older patients with multimorbidity. Methods/design: The study was designed in several steps. First, a systematic review established which outcomes were measured in published and ongoing clinical trials of medication review in older patients. Second, we undertook semistructured interviews with older patients and carers aimed at identifying additional relevant outcomes. Then, a multilanguage European Delphi survey adapted to older patients was designed. The international Delphi survey was conducted with older patients, health care professionals, researchers, and clinical experts in geriatric pharmacotherapy to validate outcomes to be included in the core outcome set. Consensus meetings were conducted to validate the results. Discussion: We present the method for developing a core outcome set for medication review in older patients with multimorbidity. This study protocol could be used as a basis to develop core outcome sets in other fields of geriatric research. Keywords: core outcome set, study protocol, polypharmacy, multimorbidity

CONTRIBUTORS IN THE NETWORK OF TEACHERS IN PHARMACOTHERAPY (NOTIP) (ALPHABETIZED BY COUNTRY): Atanasova, Ivanka (Sofia University St. Kliment Ohridski, Sofia, Bulgaria); Ganeva, Maria (Trakia University, Stara Zagora, Bulgaria); Gatchev, Emil (Medical University of Sofia, Sofia, Bulgaria); Kostadinova, II (Medical University Plovdiv, Plovdiv, Bulgaria); Mimica Matanovic, S (University of Osijek, Osijek, Croatia); Vitezic, D (University of Rijeka Medical School, Rijeka, Croatia); Wozniak, Greta (University of Cyprus, Nicosia, Cyprus); Kmonickova, E (Charles University, Pilsen, Czech Republic); Urbanek, Karel (Palacky University, Olomouc, Czech Republic); Damkier, P (University of Southern Denmark, Odense, Denmark); Huupponen, RK (University of Turku, Turku, Finland); Auffret, Marine (Hospices civils de Lyon, Lyon, France); Bejan-Angoulvant, T (Université de Tours, Tours, France); Chouchana, Laurent (Hospital Cochin, Paris, France); Cracowski, Jean-Luc (University Grenoble Alpes, La Tronche, France); Drici, MD (University of Nice Côte d'Azur, Nice, France); Faillie, JL (CHU Montpellier, Montpellier, France); Geniaux, Hélène (CHU de Limoges, Limoges, France); Molimard, M (Université de Bordeaux, Bordeaux, France); Orlikowski, D (Versailles Saint-Quentin-en-Yvelines University, Versailles, France); Palin, Karine (University of Bordeaux, Bordeaux, France); Pers, Y-M (CHU Montpellier, Montpellier, France); Picard, Nicolas (CHU de Limoges, Limoges, France); Simon, N (Aix-Marseille University, Marseille, France); Toussirot, E (CHU de Besancon, Besancon, France); Boger, RH (University Medical Center Hamburg-Eppendorf, Hamburg, Germany); Cascorbi, I (University of Kiel, Kiel, Germany); Mueller, SC (University Medicine Rostock, Rostock, Germany); Regenthal, R (University of Leipzig, Leipzig, Germany); Schwab, M (Eberhard Karl University of Tübingen, Tübingen, Germany); Schwaninger, MS (University of Luebeck, Luebeck, Germany); Thuermann, PA (University Witten/Herdecke, Witten, Germany); Wojnowski, L (University Medical Center Mainz, Mainz, Germany); Kouvelas, D (Aristotle University of Thessaloniki, Thessaloniki, Greece); Riba, P (Semmelweis University, Budapest, Hungary); Kerins, David M (University College, Cork, Ireland); Williams, David J (Royal College of Surgeons in Ireland, Dublin, Ireland); Cosentino, M (University of Insubria, Varese, Italy); De Ponti, Fabrizio (University of Bologna, Bologna, Italy); Filippelli, Amelia (University of Salerno, Baronissi, Italy); Leone, R (University of Verona, Verona, Italy); Locatelli, Vittorio (University of Milano - Bicocca, Monza, Italy); Jansone, Baiba (University of Latvia, Riga, Latvia); Gulbinovic, Romaldas (Vilnius University, Vilnius, Lithuania); Mifsud, Janet (University of Malta, Msida, Malta); Braszko, Jan J (Medical University of Bialystok, Bialystok, Poland); kocic, I (Medical University of Gdansk, Gdansk, Poland); Breitenfeld, Luiza (Beira Interior University, Covilh~a, Portugal); Castelo-Branco, M (University of Beira Interior, Covilh~a, Portugal); Conea, Simona (“Vasile Goldis” Western University of Arad, Arad, Romania); Magyar, Ioan (University of Oradea, Oradea, Romania); Bevc, S (University of Maribor, Maribor, Slovenia); Krzan, Mojca (University of Ljubljana, Ljubljana, Slovenia); Bernal, ML (University of Zaragoza, Zaragoza, Spain); Capellà, D (University of Girona, Girona, Spain); Carcas, A (Universidad Autónoma de Madrid, University of Maribor, Spain); De Abajo, FJ (University of Alcalá, Alcalá de Henares, Spain); Lopez-Rico, M (University of Salamanca, Salamanca, Spain); Lucena, MI (University of Malaga, Malaga, Spain); Pontes, C (Universitat Autonoma de Barcelona, Sabadell, Spain); Sanz, EJ (Universidad de La Laguna, La Laguna, Spain); Böttiger, Y (Linköping University, Linköping, Sweden); Le Grevès, Madeleine (Uppsala University, Uppsala, Sweden); de Waard-Siebinga, I (University Medical Center Groningen, Groningen, The Netherlands); Janssen, Ben JA (Maastricht University, Maastricht, The Netherlands); Knol, Wilma (University Medical Center Utrecht, Utrecht, The Netherlands); Pandit, Rahul (University Medical Center Utrecht, Utrecht, The Netherlands); van Rosse, F (Erasmus Medical Center, Rotterdam, The Netherlands); Dent, G (Keele University, Keele, United Kingdom); Ferro, Albert (King's College London, London, United Kingdom); Hitchings, AW (St George's, University of London, London, United Kingdom); Kapil, V (Queen Mary University London, London, United Kingdom); Linton, KD (University of Sheffield, Sheffield, United Kingdom); Loke, YK (University of East Anglia, Norwich, United Kingdom); Okorie, Michael (Brighton and Sussex Medical School, Brighton, United Kingdom); Plumb, Richard David (Queen's University Belfast, Belfast, United Kingdom); Pontefract, Sarah (University of Birmingham, Birmingham, United Kingdom); Ranmuthu, S (Queen Mary University London, London, United Kingdom); Sampson, AP (University of Southampton, Southampton, United Kingdom); Thanacoody, HKR (Newcastle University, Newcastle upon Tyne, United Kingdom); Whitfield, Jonathan P (University of Aberdeen, Aberdeen, United Kingdom); Wilson, Kurt (University of Manchester, Manchester, United Kingdom) Improvement and harmonization of European clinical pharmacology and therapeutics (CPT) education is urgently required. Because digital educational resources can be easily shared, adapted to local situations and re‐used widely across a variety of educational systems, they may be ideally suited for this purpose Methods With a cross‐sectional survey among principal CPT teachers in 279 out of 304 European medical schools, an overview and classification of digital resources was compiled. Results Teachers from 95 (34%) medical schools in 26 of 28 EU countries responded, 66 (70%) of whom used digital educational resources in their CPT curriculum. A total of 89 of such resources were described in detail, including e‐learning (24%), simulators to teach pharmacokinetics and/or pharmacodynamics (10%), virtual patients (8%), and serious games (5%). Together, these resources covered 235 knowledge‐based learning objectives, 88 skills, and 13 attitudes. Only one third (27) of the resources were in‐part or totally free and only two were licensed open educational resources (free to use, distribute and adapt). A narrative overview of the largest, free and most novel resources is given. Conclusion Digital educational resources, ranging from e‐learning to virtual patients and games, are widely used for CPT education in EU medical schools. Learning objectives are based largely on knowledge rather than skills or attitudes. This may be improved by including more real‐life clinical case scenarios. Moreover, the majority of resources are neither free nor open. Therefore, with a view to harmonizing international CPT education, more needs to be learned about why CPT teachers are not currently sharing their educational materials.

AIMS: Medication safety requires urgent attention in hospital pharmacy. This study evaluated the medication-related problems/errors as reported to the Dutch medication incident registry and disseminated for information to pharmacists. Through analysis by an expert panel we aimed to better understand which problems could have been mitigated by the drug product design. Additionally, the (wider) implications of the problems for current hospital/clinical practice were discussed.METHODS: Items were extracted from the public Portal for Patient Safety. Items were included if relevant for older people and connected with the drug product design and excluded if they should reasonably have been intercepted by compliance to routine controls or well-known professional standards in pharmaceutical care. To explore any underreporting of well-known incidents, it was investigated if different medication-related problems could be observed in a regional hospital practise over a 1-month period. For 6 included items (cases), the implications for hospital/clinical practise were discussed in an expert panel.RESULTS: In total, 307 items were identified in the Portal for Patient Safety; all but 14 were excluded. Six cases were added from daily hospital practice. These 20 cases commonly related to confusing product characteristics, packaging issues such as the lack of a single unit package for an oncolytic product, or incorrect or incomplete user instructions.CONCLUSION: Medication registries provide important opportunities to evaluate real-world medication-related problems. However, underreporting of well-known problems should be considered. The product design can be used as an (additional) risk mitigation measure to support medication safety in hospital practice.

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

Achieving appropriate medication is a multidimensional process. Current research on polypharmacy mainly focuses on drug appropriateness, but little is devoted to what determines the ongoing challenge. The authors, with their diverse clinical, pharmaceutical and regulatory backgrounds, offer a narrative review on the causes of inappropriate polypharmacy and how to avoid it. Inappropriate polypharmacy may stem from the systematic exclusion of frail older patients from landmark randomised controlled trials, which has prevented the accurate establishment of the clinical benefits of a drug for that ever-growing group of patients. Nonetheless, what may determine the usefulness of a drug in a specific patient cohort is its design. Patient-centric drug product development must, therefore, account for older people's characteristics, so that drugs are better formulated from their inception. This novel drug development process has significant implications for industry and requires adequate regulation. Clinicians must understand and be part of drug development. Explicit criteria such as STOPP/START provide guidance on identifying opportunities and circumstances to review medication but achieving appropriateness is far more complicated. New healthcare technology may pave the way to better-tailored interventions at a healthcare system level, but patient and advocate voices, as well as communication and continuity of care, must remain at the core. In conclusion, inappropriate polypharmacy results from the combination of multiple factors. Achieving appropriate medication for older adults requires merging different disciplines and a focus on patients’ needs and expectations.

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

PURPOSE: To determine whether glucose variability is altered during delirium days compared to non-delirious days in critically ill patients with and without diabetes in the intensive care unit (ICU). MATERIALS AND METHODS: Critically ill patients with delirious and non-delirious days during ICU stay were included from a prospective cohort study which was conducted from January 2011- June 2013. Glucose variability was measured each observation day using various definitions (change in mean glucose, standard deviation, mean absolute glucose, daily delta and occurrence of hypo- and hyperglycemia). Mixed-effects models and generalized mixed-effects models with logit link function were performed to study the association between delirium and glucose variability, adjusting for potential confounders. RESULTS: With the exception of the risk of hypoglycemia, delirium was not linked to higher glucose variability using the various definitions of this estimate. For hypoglycemia, we did find an association with delirium in diabetic patients (OR adj.: 2.78; 95% CI: 1.71-6.32, p = 0.005), but not in non-diabetic patients (OR adj.: 1.16; 95% CI: 0.58-2.28, p = 0.689). CONCLUSIONS: Despite the positive association between delirium and hypoglycemia in critically ill patients with diabetes, delirium was not associated with more pronounced glucose variability. Our findings suggest that glucose levels should be monitored more closely in diabetic patients during delirium at the ICU to prevent hypoglycemia.

Objective Antipsychotics may disrupt metabolic regulation in patients with diabetes mellitus. The risk of hypoglycemia in older users of antipsychotics with diabetes is largely unknown. Therefore, we investigated the association between the use of antipsychotic drugs and hypoglycemia requiring hospital admission in older patients with diabetes. Methods In a nested case-control study using community pharmacy records linked to hospital admission data in the Netherlands (1998–2008), a cohort of 68,314 patients at least 65 years with diabetes was studied. Cases were patients from the study cohort with a first hospital admission for hypoglycemia; up to five comparison subjects were selected for each case. Exposure to antipsychotic drugs was the primary determinant of interest. Logistic regression analysis was performed to estimate the strength of the association between antipsychotic drug use and hypoglycemia, taking into account potential confounders. Results Eight hundred fifteen patients were admitted to hospital for hypoglycemia. Current use of antipsychotic drugs was associated with an increased risk of hypoglycemia compared with non-use (adjusted OR: 2.26; 95% CI: 1.45–3.52; Wald χ 2 = 13.08, df = 1, p ≤0.001), especially in the first 30 days of treatment (adjusted OR: 7.65; 95% CI: 2.50–23.41; Wald χ 2 = 12.72, df = 1, p ≤0.001) and with higher doses (adjusted OR: 8.20; 95% CI: 3.09–21.75; Wald χ 2 = 17.90, df = 1, p ≤0.001). Conclusion Use of antipsychotic drugs by older patients with diabetes mellitus was associated with an increased risk of hospitalization for hypoglycemia. Our findings suggest that glucose levels should be monitored closely after initiation of antipsychotic drugs.

Objective: To assess the efficacy of medication review as an isolated intervention and with several co-interventions for preventing hospital readmissions in older adults. Methods: Ovid MEDLINE, Embase, The Cochrane Central Register of Controlled Trials and CINAHL were searched for randomized controlled trials evaluating the effectiveness of medication review interventions with or without co-interventions to prevent hospital readmissions in hospitalized or recently discharged adults aged ≥65, until September 13, 2019. Included outcomes were “at least one all-cause hospital readmission within 30 days and at any time after discharge from the index admission.” Results: Twenty-five studies met the inclusion criteria. Of these, 11 studies (7,318 participants) contributed to the network meta-analysis (NMA) on allcause hospital readmission within 30 days. Medication review in combination with (a) medication reconciliation and patient education (risk ratio (RR) 0.45; 95% confidence interval (CI) 0.26–0.80) and (b) medication reconciliation, patient education, professional education and transitional care (RR 0.64; 95% CI 0.49–0.84) were associated with a lower risk of all-cause hospital readmission compared to usual care. Medication review in isolation did not significantly influence hospital readmissions (RR 1.06; 95% CI 0.45–2.51). The NMA on allcause hospital readmission at any time included 24 studies (11,677 participants). Medication review combined with medication reconciliation, patient education, professional education and transitional care resulted in a reduction of hospital readmissions (RR 0.82; 95% CI 0.74–0.91) compared to usual care. The quality of the studies included in this systematic review raised some concerns, mainly regarding allocation concealment, blinding and contamination. Conclusion: Medication review in combination with medication reconciliation, patient education, professional education and transitional care, was associated with a lower risk of hospital readmissions compared to usual care. An effect of medication review without co-interventions was not demonstrated. Trials of higher quality are needed in this field.