Drug Safety for Nursing-Home Residents
Findings of a pragmatic, cluster-randomized, controlled intervention trial in 44 nursing homes
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Background: The safety of drug use by nursing-home residents can be impaired by polypharmacy, potentially inappropriate medications (PIM), and neuroleptics, as well as by a lack of adequate interprofessional coordination in the nursing home. The goal of the HIOPP-3-iTBX Trial was to improve drug safety in nursing-home residents, including a reduction of PIM and/or neuroleptic use, by means of a complex interprofessional intervention.
Methods: This cluster-randomized, controlled trial was performed in nursing homes in Germany. Residents over age 65 were included in the trial. The intervention was carried out over six months and consisted of four elements: a drug review by trained pharmacists, educational sessions for general practitioners and nurses, a drug safety toolbox, and change management seminars for members of the three participating professions. The nursing homes in the control group continued to provide usual care. The primary endpoint was the prescription of at least one PIM and/or at least two neuroleptic drugs simultaneously. The secondary endpoints were the incidence of falls and hospitalizations, quality of life, and health-care costs. This trial is registered in the German Clinical Trials Registry (DRKS00013588).
Results: 44 nursing homes with 862 residents were randomized, 23 of them (with 452 residents) to the intervention group and 21 (with 410 residents) to the control group. 41% of all nursing-home residents initially took at least one PIM and/or at least two neuroleptic drugs simultaneously. Follow-up data (including, among other things, the current drug regimen) were obtained for 773 residents. The intention-to-treat analysis continued to show no difference between the intervention group and the control group with respect to the primary endpoint.
Conclusion: This trial of an intervention to improve drug safety in nursing homes led neither to reduced prescribing of PIM and/or neuroleptic drugs, nor to any improvement in the overall health status of the nursing-home residents.
The majority of nursing-home residents are exposed to polypharmacy (concurrent use of five or more different medications) (1). Polypharmacy is associated with an increased risk for adverse drug events (ADEs), more falls, higher hospitalization rates, and higher risk of mortality (2). In addition, nursing-home residents are far more likely to use potentially inadequate medications (PIM) compared to elderly people living at home (3). In conjunction with a fragile physical disposition (for example, frailty), PIM are associated with a particularly high risk for ADEs (4, 5). Psychopharmacological drugs (including antidepressants, neuroleptic drugs, and benzodiazepines) also merit specific attention. Approximately 50% of nursing-home residents receive neuroleptic drugs (6) that have been shown to be associated with cardiovascular events and hip fractures, as well as well with higher all-cause mortality (7, 8).
Drug management poses a challenge not only with regard to polypharmacy and the prescription of PIM/neuroleptic drugs, but also in terms of the collaboration between the professionals involved (9). To date, there has been little instruction on interprofessional drug management; recommendations, such as the use of a “drug therapy safety card” by nursing staff, are profession-specific (10). Structured pathways of collaboration and information sharing are not mandatory for general practitioners, physicians in other specialties, pharmacists, or nurses, nor are medication reviews required (11).
Efforts have been made meanwhile to improve drug therapy safety for nursing-home residents, and to demonstrate their effects in randomized controlled trials (RCTs). Three reviews carried out in the years 2010–2012 of the handful of RCTs conducted up to that time found evidence that while effective collaboration or medication reviews can reduce inadequate prescribing, this produced no health benefits (12, 13, 14). According to Alldred et al., the available evidence is based on studies of insufficient methodological quality and, therefore, does not permit reliable conclusions to be drawn (14). More recently, additional cluster-randomized studies (cRCTs) from the European area have been published (15, 16, 17), demonstrating optimization of medication in nursing-home residents, although two studies found no improvement in the clinical endpoints (15, 16). The COSMOS study (17), in contrast, showed an improvement in quality of life as well as activities of daily living functions among participants.
The HIOPP-3-iTBX study (HIOPP, primary care initiative to optimize patient safety in polypharmacy; iTBX, interprofessional toolbox) is the first cRCT on medication optimization in nursing homes in Germany (18). Preliminary studies (19, 20, 21) used a variety of interventional elements (medication reviews, further training for nursing staff, physicians, and pharmacists, as well as a toolbox). These were further developed as part of the project and supplemented with moderated change management seminars for the three professional groups involved.
The aim of this study was to increase drug therapy safety by reducing the proportion of nursing-home residents using ≥ one PIM and/or ≥ two neuroleptic drugs through complex, multiprofessional interventions, including medication reviews.
Between May 2018 and July 2019, a cluster-randomized controlled intervention study was conducted in nursing homes. In a first step, four centers (the Institutes for General Practice in Düsseldorf, Hannover, Rostock, and Tübingen) recruited nursing homes with care agreements according to § 72 of Book XI of the German Social Code (SGB). Each home formed a cluster, meaning that the residents were either fully in the invention arm or fully in the control arm. This was to prevent contamination occurring between intervention and routine measures.
Firstly, all nursing homes in the Hannover, Düsseldorf, and Tübingen regions, as well as in the federal state of Mecklenburg-Western Pomerania, were contacted. All treating general practitioners and pharmacists in the interested nursing homes were approached. Only if a multiprofessional team could be formed from these professionals were the residents of the respective nursing home approached. The inclusion criterion for participants was age ≥ 65 years. Exclusion criteria included: no consent from the resident or their legal guardian, short-term care, and a life expectancy of less than 6 months. Detailed information on the recruitment process can be found in Kirsch et al. (22).
The multiprofessional HIOPP-3-iTBX intervention comprised elements I–IV shown in the Box.
- The first of these elements was the mandatory pharmaceutical medication review (23). The pharmacists supplying the nursing homes performed a one-off review for each nursing-home resident in the intervention group. To this end, they used the German ATHINA assessment criteria (drug therapy safety in pharmacies) (24) in the context of a more advanced medication analysis (type 2b). The pharmacists then faxed a form with their recommendations (Med-Check fax) to the responsible general practitioners, who decided on treatment changes.
- The second element consisted of training sessions or continuing education. All pharmacists were required to participate in the ATHINA advanced training program organized by the German Chambers of Pharmacists, where they learned the requirements for the medication review, as well as a 1-day study-related training session on the problems of medications in nursing-home residents. The advanced training programs for general practitioners and nursing staff were optional. General practitioners could take part in a 2-h group training session on the topic of “Drug therapy safety in nursing homes” or, alternatively, a personal training session (in person/by telephone). Nursing staff were offered two training sessions on frequent medication-specific adverse effects in nursing homes.
- The third intervention element comprised the interprofessional toolbox: a collection of materials to promote collaboration as well as to be used to look up drug-related risks.
- Finally, all professionals affiliated to nursing homes in the intervention group attended three change management seminars over the course of the intervention.
Professionals in the control group did not receive any measures. Detailed information on the complex intervention can be found in eMethods Section 1 and the eTable.
The primary endpoint was the proportion of nursing-home residents that were using at least one PIM and/or at least two neuroleptic drugs 6 months following the baseline survey. Secondary endpoints related to the following variables: fall incidence, hospitalizations, quality of life, and health economic outcomes.
Study personnel carried out two surveys in nursing homes in both the intervention arm and in the control arm: one shortly before the intervention (T0) and one at the end of the intervention phase at 6 months (T1). In addition to patients’ current medication plans, the following were collected from the nursing records for the preceding 6 months: fall events, diagnoses, number and duration of hospitalizations, and uptake of other health services. Furthermore, using an extensive list of symptoms (20 items), possible adverse drugs events in nursing-home residents were recorded either from the residents themselves or based on third-party accounts. The EQ-5D-3L questionnaire was used to determine health-related quality of life.
Nursing homes were randomized to the intervention or to the control arm by an independent person using block randomization with stratification by centers and number of subjects per home and were included parallel in time. Blinding was not possible due to the design of the intervention. Further details on the methodology of the study can be found in the eMethods Section.
Of the 524 nursing homes contacted in the four regions, 69 agreed to participate (for details see ). Ultimately, 44 nursing homes with 862 residents were randomized. A total of 23 nursing homes with 452 participants were assigned to the intervention group (IG) and 21 nursing homes with 410 participants to the control group (CG). In all, 787 residents could be surveyed for the baseline assessment (402 IG, 385 CG). The follow-up assessment could not be performed in a total of 133 residents (78 in the IG and 55 in the CG). Nevertheless, the medication plan was recorded as the primary endpoint in 119 of these subjects that dropped out, meaning that 773 participants (399 in the IG and 374 in the CG) were included in the intention-to-treat analysis (ITT). In addition to the subjects that dropped out, it was also not possible to carry out the intervention according to the protocol in seven residents, meaning that altogether 647 residents (317 in the IG and 330 in the CG) were included in the per-protocol analysis (PP) (Figure).
Table 1 shows the baseline survey (787 residents) in detail. Half of residents had been living in their nursing home for at least 29 months. The average age was 84 years and residents were predominantly female. Two thirds of residents were deemed to be suffering from dementia (according to the judgment of nursing staff, medical records, or the general practitioner). Approximately 80% of residents were moderately to severely impaired in terms of the Barthel index for activities of daily living. On average, general practitioners reported seven of 36 predefined chronic disorders for their patients. The most frequent diagnoses included arterial hypertension, dementia, osteoarthritis, heart failure, renal failure, dyslipidemia, depression, and diabetes mellitus. In all, 50% of residents used 11 or more prescription medications (including on-demand medication), thereby exhibiting excessive polypharmacy. A total of 41% of participants concurrently used at least one PIM and/or at least two neuroleptic drugs. Intervention patients did not differ significantly from control patients in terms of characteristics (Table 1).
For the follow-up investigation, the most recent medication plans of 773 nursing-home residents (399 in the IG and 374 in the CG) were evaluated. The percentage of residents using at least one PIM and/or at least two neuroleptic drugs did not differ between the two groups (Table 2); the percentage in the IG was 40.6% and in the CG 40.4%. In mixed model 1, the homes were accounted for as a random effect; in model 2, the variables age, sex, dementia, number of illnesses, and use of ≥ one PIM and/or ≥ two neuroleptic drugs were additionally included at baseline. Even after adjusting for these variables, no differences were found for the primary endpoint. A sensitivity analysis with the “per protocol” population also yielded no significant differences (Table 2).
Secondary endpoints were recorded in the follow-up assessment by survey and using the documentation from the nursing home records. Since full follow-up was not possible in 140 nursing-home residents, an evaluation of the per-protocol population was carried out.
Over the 6-month observation period, 39% of residents in the intervention arm and 30% of residents in the control arm experienced at least one fall. The results of the mixed ordinal logistic models clearly show that allocation to the intervention or to the control group had no effect on the number of fall events. Similarly, there were no significant differences in terms of the number of hospitalizations or the proportion of nursing-home residents requiring emergency or rescue services on at least one occasion in the preceding 6 months. Participants in the intervention arm also showed no notably different quality of life (Table 3). The overall costs will be presented in a separate publication.
The complex intervention used in the HIOPP-3-iTBX study to increase drug therapy safety for nursing-home residents consisted of a mandatory medication review and the optional elements of further training, tools to increase awareness of drug therapy safety and to overcome interprofessional/intersectorial boundaries, as well as change management seminars to optimize collaboration. In the intervention nursing homes, these measures resulted neither in less prescribing of PIM and/or neuroleptic drugs nor in a measurable improvement in the health status of residents.
Medication management in nursing homes is an elaborate process: it begins with establishing the indication for a medication and ends with its use by the nursing-home residents, as well as with health checks. In addition to residents and their relatives, this process involves general practitioners, other medical specialists (for example, neurologists, psychiatrists, and urologists), pharmacists, and nurses, and possibly also additional centers, such as service providers who package medications in blister packs for patients on an individual basis (26). Also, nursing-home residents have free choice of physician, leading to a large amount of contact between carers and various (primary care) physicians (9). Furthermore, care culture and boundary conditions, such as nursing staff resources and drug discount contracts, affect the process (9).
The complex HIOPP-3-iTBX intervention was developed and elaborated in preliminary studies taking these factors into account. Nevertheless, this study was unable to demonstrate a relevant effect. A number of limiting factors already became evident during the study. As also observed in the preliminary AMTS I and AMTS-Ampel studies (19, 20), some general practitioners had difficulty complying with the HIOPP-3-iTBX intervention in all its aspects. For example, the participation rate among physicians at the three consecutive change management seminars fell to 46%, whereas the final seminar was still attended by 60% of the nursing staff originally present and 75% of pharmacists. It is possible that this situation was contributed to by the increasing work demands on primary care practices due to a lack of general practitioners, as well as by the prioritization of tasks within practices (27).
In addition, a comparatively low rate of adoption by physicians of recommendations made by pharmacists was observed. For example, written feedback was provided by general practitioners for 239 of the 360 medication reviews carried out by pharmacists in the intervention group. The pharmacists initially proposed that 939 (32.4%) of the medications reviewed required optimization. The general practitioners responded to 590 proposals: they accepted recommendations for 153 medications (25.9%), wanted to potentially respond at a later point regarding 176 medications (29.8%), and made no changes at all for 349 proposals.
Whereas pharmacists focus on drug therapy safety, general practitioners additionally need to consider other factors such as clinical need in the absence of better alternatives, as well as the expectations of residents and/or their relatives, nursing home staff, and co-treating specialists. However, experience gained in local initiatives shows that direct contact and personal collaboration between physicians and pharmacists can lead to greater acceptance of their mutual expertise (28). Ultimately, it is the vulnerable and changing health status of the nursing-home residents themselves that consistently prompts changes in medication. The extent to which an initially one-off medication review can have a sustained effect under these ever-changing conditions is unclear.
Review articles assess with caution the effects on optimizing home medication due to the variability and quality of outcomes in two respects: on the one hand one sees indications of improved quality of medication, and on the other virtually no effects on the health status of residents. Recently published randomized controlled studies from Europe (15, 16, 17) confirm these previous findings. In contrast to our study, they demonstrate improved drug therapy safety. However, the medication endpoints relate to the reduction in the number of medications, PIM, or PIM and potentially underprescribed medications. Only the COSMOS study (17) specifically deals with psychotropic drugs, with no sustained change being apparent, much like the current PROPER study, in which the reduction in psychotropic drugs in the nursing home was the primary objective (29). Positive effects on health status are demonstrated only in the COSMOS study in terms of quality of life, activities of daily living (ADL) function, and mental health symptoms (agitation). In addition to a medication review, the intervention also included non-pharmacological measures. It is possible that for nursing-home residents in particular, a comprehensive intervention approach of this kind in combination with drug therapy safety management is effective.
Strengths and limitations
With 862 residents recruited from 44 nursing homes, the requisite high number of cases was achieved despite the prevailing challenges. However, it is possible that there may have been an unintentional selection of the primarily interested nursing homes, pharmacists, and general practitioners.
Attention was paid to ensure that the HIOPP-3-iTBX study adhered to the principles of a pragmatic intervention under routine practice conditions, as also reflected in the realistic further training times. Therefore, although it is not possible to demonstrate maximum potential effectiveness, the “real” effectiveness that can be expected in the routine care setting can be shown (30). This has once again highlighted how challenging it is to implement a complex intervention that requires harmonious multiprofessional communication and collaboration under the prevailing conditions of fragmentation and delineation of tasks in medication management (26, 28, 31).
The selected 6-month duration of follow-up can be evaluated critically on the one hand with regard to demonstrating effectiveness. It is possible that at the time of the follow-up survey the complex interventions had not yet been consolidated. However, the generally high mortality rate among nursing-home residents and higher study costs were arguments against a longer follow-up. Comparable nursing home studies have follow-up periods of between 6 weeks and 24 months (14, 15, 16, 17). On the other hand, the primary endpoint chosen by us, “reduction in PIM and neuroleptic drugs,” was possibly not tailor-made for the broad-based intervention. A recommendation that has since been published on the selection of endpoints to demonstrate the effectiveness of medication reviews suggests, moreover, that too little attention has been paid to the expectations of elderly patients in previous medication studies (32).
Funding and registration
The HIOPP-3-iTBX study was funded by the Innovation Fund of the Joint Federal Committee (Grant No.: 01VSF16017). The Ethics Committee of the Hannover Medical University approved the Masters Ethics Application (No. 7655). The study was registered in the German Register of Clinical Trials (DRKS00013588).
Members of the HIOPP-3-iTBX study group
Dr. Simone Bernard, Prof. Petra Thürmann, Philipp Klee Institut für Klinische Pharmakologie, Universität Witten/Herdecke; Stefanie Kortekamp, Evangelische Hochschule Rheinland-Westfalen-Lippe; Angela Fuchs, Prof. Achim Mortsiefer, Prof. Stefan Wilm, Institut für Allgemeinmedizin, Heinrich-Heine Universität Düsseldorf; Dr. Anja Wollny, Lisa Sparenberg, Franziska Rebentisch, Prof. Attila Altiner, Institut für Allgemeinmedizin, Universitätsklinik Rostock; Regina Stolz, Dr. Hannah Haumann, Heidi Riescher, Prof. Stefanie Joos, Institut für Allgemeinmedizin und Interprofessionelle Versorgung, Universitätsklinik Tübingen; Birgitt Wiese, Prof. Ulrike Junius-Walker, PD Dr. Olaf Krause, Dr. Ina-Merle Doyle, Claudia Kirsch, Svetlana Usacheva, Trang Le, Silke Mamone, Prof. Nils Schneider, Institut für Allgemeinmedizin, Medizinische Hochschule Hannover; Dr. Antje Freytag, Institut für Allgemeinmedizin, Universitätsklinikum Jena; Dr. Thomas G. Grobe, Jona Frasch, Mike Klora, Sina Weinand, aQua-Institut für angewandte Qualitätsförderung und Forschung im Gesundheitswesen GmbH, Göttingen; Christian Günster, WIdO Institut, Berlin.
We would like to thank all participating nursing homes as well as participating nursing-home residents and their carers. We would also like to thank all nursing staff in the homes, as well as all nursing services, general practitioners, medical assistants, and pharmacists for their participation. Our thanks also go to Julia Fabricius, Magdalene Linz, Carina John, Patrick Schäfer, and Christian Gillot from the regional chambers of pharmacists in Lower Saxony, North Rhine-Westphalia, Baden-Württemberg, and Mecklenburg-Western Pomerania for their tremendous support of the project.
Data sharing statement
Based on the informed consent statements provided by the nursing-home residents, the data can be reported in aggregate form only.
Conflict of interest statement
The authors declare that no conflict of interest exists.
Manuscript received on 24 February 2021, revised version accepted on 14 July 2021.
Translated from the original German by Christine Rye.
PD Dr. med. Olaf Krause
Medizinische Hochschule Hannover
Institut für Allgemeinmedizin
Carl-Neuberg-Straße 1, 30625 Hannover, Germany
Cite this as
Junius-Walker U, Krause O, Thürmann P, Bernhard S, Fuchs A, Sparenberg L, Wollny A, Stolz R, Haumann H, Freytag A, Kirsch C, Usacheva S, Wilm S, Wiese B, on behalf
of the HIOPP-3-iTBX study group: Drug safety for nursing-home residents—findings of a pragmatic, cluster-randomized, controlled intervention trial in 44 nursing homes.
Dtsch Arztebl Int 2021; 118: 705–12. DOI: 10.3238/arztebl.m2021.0297
eMethods Section, eTable:
*2 These two authors share last authorship.
Institute for General Practice, Hannover Medical School: Prof. Dr. med. Ulrike Junius-Walker, PD Dr. med. Olaf Krause, Claudia Kirsch, Svetlana Usacheva, Dipl.-Math. Birgitt Wiese
Medical Rehabilitation and Geriatrics, Hospital DIAKOVERE Henriettenstift, Hannover:
PD Dr. med. Olaf Krause
Philipp Klee Institute for Clinical Pharmacology, University of Witten/Herdecke, Wuppertal:
Prof. Dr. med. Petra Thürmann, Dr. rer. nat. Simone Bernard
Institute for General Practice, Heinrich-Heine University Düsseldorf: Angela Fuchs, Prof. Dr. med. Stefan Wilm
Institute of General Practice, Rostock University Medical Center: Lisa Sparenberg, Dr. phil. Anja Wollny
Institute for General Medicine and Inter professional Care, Tübingen University Hospital: Regina Stolz, M.A., Dr. med. Hannah Haumann
Institute of General Practice and Family Medicine, Jena University Hospital: Dr. rer. pol. Antje Freytag
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