Potentially inappropriate medication including drug-drug interaction and the risk of frequent falling, hospital admission, and death in older adults - results of a large cohort study (getABI).

Introduction: With growing age, multiple chronic diseases may result in polypharmacy. Drugs that should be avoided in older adults are called potentially inappropriate medications (PIM). Beyond PIM, drug-drug interactions (DDI) are known to be related to adverse drug events. This analysis examines the risk of frequent falling, hospital admission, and death in older adults associated with PIM and/or DDI (PIM/DDI) prescription. Materials and methods: This post hoc analysis used data of a subgroup of the getABI study participants, a large cohort of community-dwelling older adults. The subgroup comprised 2120 participants who provided a detailed medication report by telephone interview at the 5-year getABI follow-up. The risks of frequent falling, hospital admission, and death in the course of the following 2 years were analysed by logistic regression in uni- and multivariable models with adjustment for established risk factors. Results: Data of all 2,120 participants was available for the analysis of the endpoint death, of 1,799 participants for hospital admission, and of 1,349 participants for frequent falling. The multivariable models showed an association of PIM/DDI prescription with frequent falling (odds ratio (OR) 1.66, 95% confidence interval (CI) 1.06-2.60, p = 0.027) as well as with hospital admission (OR 1.29, 95% CI 1.04-1.58, p = 0.018), but not with death (OR 1.00, 95% CI 0.58-1.72, p = 0.999). Conclusion: PIM/DDI prescription was associated with the risk of hospital admission and frequent falling. No association was found with death by 2 years. This result should alert physicians to provide a closer look at PIM/DDI prescriptions.

Predicting negative health outcomes in older general practice patients with chronic illness: Rationale and development of the PROPERmed harmonized individual participant data database.

The prevalence of multimorbidity and polypharmacy increases significantly with age and are associated with negative health consequences. However, most current interventions to optimize medication have failed to show significant effects on patient-relevant outcomes. This may be due to ineffectiveness of interventions themselves but may also reflect other factors: insufficient sample sizes, heterogeneity of population. To address this issue, the international PROPERmed collaboration was set up to obtain/synthesize individual participant data (IPD) from five cluster-randomized trials. The trials took place in Germany and The Netherlands and aimed to optimize medication in older general practice patients with chronic illness. PROPERmed is the first database of IPD to be drawn from multiple trials in this patient population and setting. It offers the opportunity to derive prognostic models with increased statistical power for prediction of patient-relevant outcomes resulting from the interplay of multimorbidity and polypharmacy. This may help patients from this heterogeneous group to be stratified according to risk and enable clinicians to identify patients that are likely to benefit most from resource/time-intensive interventions. The aim of this manuscript is to describe the rationale behind PROPERmed collaboration, characteristics of the included studies/participants, development of the harmonized IPD database and challenges faced during this process.

A prognostic model predicted deterioration in health-related quality of life in older patients with multimorbidity and polypharmacy.

OBJECTIVES: To develop and validate a prognostic model to predict deterioration in health-related quality of life (dHRQoL) in older general practice patients with at least one chronic condition and one chronic prescription. STUDY DESIGN AND SETTING: We used individual participant data from five cluster-randomized trials conducted in the Netherlands and Germany to predict dHRQoL, defined as a decrease in EQ-5D-3 L index score of ≥5% after 6-month follow-up in logistic regression models with stratified intercepts to account for between-study heterogeneity. The model was validated internally and by using internal-external cross-validation (IECV). RESULTS: In 3,582 patients with complete data, of whom 1,046 (29.2%) showed deterioration in HRQoL, and 12/87 variables were selected that were related to single (chronic) conditions, inappropriate medication, medication underuse, functional status, well-being, and HRQoL. Bootstrap internal validation showed a C-statistic of 0.71 (0.69 to 0.72) and a calibration slope of 0.88 (0.78 to 0.98). In the IECV loop, the model provided a pooled C-statistic of 0.68 (0.65 to 0.70) and calibration-in-the-large of 0 (-0.13 to 0.13). HRQoL/functionality had the strongest prognostic value. CONCLUSION: The model performed well in terms of discrimination, calibration, and generalizability and might help clinicians identify older patients at high risk of dHRQoL. REGISTRATION: PROSPERO ID: CRD42018088129.

Are Anticholinergic Symptoms a Risk Factor for Falls in Older General Practice Patients With Polypharmacy? Study Protocol for the Development and Validation of a Prognostic Model.

Background: Cumulative anticholinergic exposure, also known as anticholinergic burden, is associated with a variety of adverse outcomes. However, studies show that anticholinergic effects tend to be underestimated by prescribers, and anticholinergics are the most frequently prescribed potentially inappropriate medication in older patients. The grading systems and drugs included in existing scales to quantify anticholinergic burden differ considerably and do not adequately account for patients' susceptibility to medications. Furthermore, their ability to link anticholinergic burden with adverse outcomes such as falls is unclear. This study aims to develop a prognostic model that predicts falls in older general practice patients, to assess the performance of several anticholinergic burden scales, and to quantify the added predictive value of anticholinergic symptoms in this context. Methods: Data from two cluster-randomized controlled trials investigating medication optimization in older general practice patients in Germany will be used. One trial (RIME, n = 1,197) will be used for the model development and the other trial (PRIMUM, n = 502) will be used to externally validate the model. A priori, candidate predictors will be selected based on a literature search, predictor availability, and clinical reasoning. Candidate predictors will include socio-demographics (e.g. age, sex), morbidity (e.g. single conditions), medication (e.g. polypharmacy, anticholinergic burden as defined by scales), and well-being (e.g. quality of life, physical function). A prognostic model including sociodemographic and lifestyle-related factors, as well as variables on morbidity, medication, health status, and well-being, will be developed, whereby the prognostic value of extending the model to include additional patient-reported symptoms will be also assessed. Logistic regression will be used for the binary outcome, which will be defined as "no falls" vs. "≥1 fall" within six months of baseline, as reported in patient interviews. Discussion: As the ability of different anticholinergic burden scales to predict falls in older patients is unclear, this study may provide insights into their relative importance as well as into the overall contribution of anticholinergic symptoms and other patient characteristics. The results may support general practitioners in their clinical decision-making and in prescribing fewer medications with anticholinergic properties.

Interactions between C-reactive protein and traditional risk factors in predicting mortality of older adults.

BACKGROUND: Elevated levels of C-reactive protein (CRP) are known to be associated with cardiovascular (CV) morbidity and mortality in older adults, however, there seems to be heterogeneity of this association across subsets of individuals. We aim to assess the effects of interactions between CRP and one of the following traditional CV risk factors regarding all-cause mortality in unselected elderly men and women: age, sex, body mass index, diabetes, and hypertension. PATIENTS AND METHODS: Three hundred and forty-four general practitioners all over Germany enrolled 6,817 unselected participants, aged 65 years or older, and performed thorough examinations, including CRP measurement at baseline (getABI study). All-cause mortality was determined in the following seven years. Cox regression analyses were done using uni- and multivariable models. RESULTS: At baseline 4,172 participants of this cohort had a CRP value of ≤ 3 mg/L (low level CRP group), 2,645 participants had a CRP value of > 3 mg/L (high level CRP group). The unadjusted hazard ratio for all-cause death of the high level CRP group compared to the low level CRP group was 1.49 (95 % confidence interval [95 %CI] 1.34 to 1.66). After adjustment for sex, age, education, peripheral artery disease/media sclerosis, other prior vascular events, smoking status, diabetes, systolic blood pressure, antihypertensive medication, body mass index, cholesterol, and statin use, the hazard ratio was 1.34 (95 %CI 1.20 to 1.50). Significant interactions with CRP were found for sex (adjusted hazard ratio 1.38, 95 %CI 1.11 to 1.72), age (0.75, 95 %CI 0.60 to 0.94), and baseline systolic blood pressure (0.64, 95 % CI 0.51 to 0.81). The interactions of CRP with body mass index and of CRP with diabetes were not significant. CONCLUSIONS: In older German adults, there seem to be effect modifications by age, sex, and arterial hypertension regarding the effect of CRP in the prediction of all-cause mortality.

Polypharmacy in chronic diseases-Reduction of Inappropriate Medication and Adverse drug events in older populations by electronic Decision Support (PRIMA-eDS): study protocol for a randomized controlled trial.

BACKGROUND: Multimorbidity is increasing in aging populations with a corresponding increase in polypharmacy as well as inappropriate prescribing. Depending on definitions, 25-50 % of patients aged 75 years or older are exposed to at least five drugs. Evidence is increasing that polypharmacy, even when guidelines advise the prescribing of each drug individually, can potentially cause more harm than benefit to older patients, due to factors such as drug-drug and drug-disease interactions. Several approaches reducing polypharmacy and inappropriate prescribing have been proposed, but evidence showing a benefit of these measures regarding clinically relevant endpoints is scarce. There is an urgent need to implement more effective strategies. We therefore set out to develop an evidence-based electronic decision support (eDS) tool to aid physicians in reducing inappropriate prescribing and test its effectiveness in a large-scale cluster-randomized controlled trial. METHODS: The "Polypharmacy in chronic diseases-Reduction of Inappropriate Medication and Adverse drug events in older populations" (PRIMA)-eDS tool is a tool comprising an indication check and recommendations for the reduction of polypharmacy and inappropriate prescribing based on systematic reviews and guidelines, the European list of inappropriate medications for older people, the SFINX-database of interactions, the PHARAO-database on adverse effects, and the RENBASE-database on renal dosing. The tool will be evaluated in a cluster-randomized controlled trial involving 325 general practitioners (GPs) and around 3500 patients across five study centres in the United Kingdom, Germany, Austria and Italy. GP practices will be asked to recruit 11 patients aged 75 years or older who are taking at least eight medications and will be cluster-randomized after completion of patient recruitment. Intervention GPs will have access to the PRIMA-eDS tool, while control GPs will treat their patients according to current guidelines (usual care) without access to the PRIMA-eDS tool. After an observation time of 2 years, intervention and control groups will be compared regarding the primary composite endpoint of first non-elective hospitalization or death. DISCUSSION: The principal hypothesis is that reduction of polypharmacy and inappropriate prescribing can improve the clinical composite outcome of hospitalization or death. A positive result of the trial will contribute substantially to the improvement of care in multimorbidity. The trial is necessary to investigate not only whether the reduction of polypharmacy improves outcome, but also whether GPs and patients are willing to follow the recommendations of the PRIMA-eDS tool. TRIAL REGISTRATION: This trial has been registered with Current Controlled Trials Ltd. on 31 July 2014 (ISRCTN10137559).

Feasibility of a multidimensional home-based exercise programme for the elderly with structured support given by the general practitioner's surgery: study protocol of a single arm trial preparing an RCT [ISRCTN58562962].

BACKGROUND: Physical activity programmes can help to prevent functional decline in the elderly. Until now, such programmes use to target either on healthy community-dwelling seniors or on elderly living in special residences or care institutions. Sedentary or frail people, however, are difficult to reach when they live in their own homes. The general practitioner's (GP) practice offers a unique opportunity to acquire these people for participation in activity programmes. We conceptualised a multidimensional home-based exercise programme that shall be delivered to the target group through cooperation between GPs and exercise therapists. In order to prepare a randomised controlled trial (RCT), a feasibility study is being conducted. METHODS: The study is designed as a single arm interventional trial. We plan to recruit 90 patients aged 70 years and above through their GPs. The intervention lasts 12 weeks and consists of physical activity counselling, a home-exercise programme, and exercise consultations provided by an exercise therapist in the GP's practice and via telephone. The exercise programme consists of two main components: 1. a combination of home-exercises to improve strength, flexibility and balance, 2. walking for exercise to improve aerobic capacity. Primary outcome measures are: appraisal by GP, undesirable events, drop-outs, adherence. Secondary outcome measures are: effects (a. motor tests: timed-up-and-go, chair rising, grip strength, tandem stand, tandem walk, sit-and-reach; b. telephone interview: PRISCUS-Physical Activity Questionnaire, Short Form-8 Health Survey, three month recall of frequency of falls, Falls Efficacy Scale), appraisal by participant, exercise performance, focus group discussion. Data analyses will focus on: 1. decision-making concerning the conduction of a RCT, 2. estimation of the effects of the programme, detection of shortcomings and identification of subgroups with contrary results, 3. feedback to participants and to GPs. CONCLUSION: A new cooperation between GPs and exercise therapists to approach community-dwelling seniors and to deliver a home-exercise programme is object of research with regard to feasibility and acceptance. In case of success, an RCT should examine the effects of the programme. A future implementation within primary medical care may take advantage from the flexibility of the programme. TRIAL REGISTRATION: Current Controlled Trials ISRCTN58562962.

Impact of preoperative treatment strategies on the early perioperative outcome in neonates with hypoplastic left heart syndrome.

OBJECTIVE: This study was undertaken to determine the impact of specific intensive care procedures on preoperative hemodynamics, incidence of preoperative organ dysfunction, and in-hospital mortality among neonates with hypoplastic left heart syndrome with pulmonary overcirculation and to assess the influence of the change in preoperative management on early postoperative outcome. METHODS: In this retrospective evaluation of 72 neonates with classic hypoplastic left heart syndrome and severe pulmonary overcirculation with different preoperative management strategies from 1992 to 1995 and from 1996 to 2000, univariate and multivariate analyses of risk factors were performed with stepwise logistic regression. RESULTS: Among patients with ventilatory and inotropic support from admission until surgery, degree of metabolic acidosis (lowest recorded and prerepair pH values) was significantly higher than among patients who received systemic vasodilators without ventilation before surgery. Preoperative organ dysfunction occurred in 19 of 72 patients (26%), predominantly before 1996; the most significant was hepatic failure in 13 (68%). Lowest recorded and prerepair pH values did not predict the development of organ dysfunction, whereas inotropic medication, lack of afterload reduction, and especially ventilatory support correlated significantly with organ injury. In-hospital mortality decreased from 65% (13/20) to 13% (6/46) from the first to the second period. According to multivariate analysis, ventilatory support and organ dysfunction were significantly related to in-hospital mortality. CONCLUSION: In neonates with hypoplastic left heart syndrome, systemic afterload reduction can avoid preoperative artificial respiration, identified as a significant risk factor for the development of preoperative dysfunction of end organs and in-hospital mortality.