This study hypothesizes that a pharmacist-led intervention involving the systematic review of pharmacotherapeutic plans in nursing home residents will improve the quality and safety of their medication regimens.

The primary objective of this study is to evaluate the effectiveness of a structured pharmaceutical intervention based on the review and optimization of pharmacotherapeutic plans to improve their appropriateness for individuals residing in nursing homes.

Specifically, the study aims to determine, over a 3-month period, the effectiveness of the program in (Meyer-Massetti et al., 2018): reducing drug-related problems (DRPs), as measured by the number of DRPs per patient and the proportion of patients with DRPs, and (Ruiz-Ramos et al., 2021) reducing polypharmacy, in terms of the average number of medications per patient and the number of patients exposed to polypharmacy.

This is a quasi-experimental study using a non-randomized cluster assignment of patients (nursing homes) into two groups: (a) an intervention group receiving a structured review and optimization of pharmacotherapeutic plans, and (b) a control group receiving usual care based on standard clinical practice (Figure 1).

The study will be conducted in the 24 nursing homes served by primary care teams from the Primary care directorate of Camp de Tarragona (Catalan health institute).

Inclusion criteria: individuals aged 65 years or older, on pharmacological treatment with at least one medication, for a period longer than 3 months. Exclusion criteria include: patients hospitalized at the time of the review, those in end-of-life care, those for whom participation may be deemed potentially harmful by the responsible physician, and patients not covered by the public healthcare or pharmacy system.

Clustering was defined at the level of the nursing home to minimize the risk of contamination, as residents within the same facility are typically treated by the same medical and care teams. Assigning entire centers to either the intervention or control group also facilitated the coordinated implementation of the structured medication review process and aligned with the organizational routines of the participating facilities.

Assignment to either the intervention or control group will be based on convenience within the context of implementing the pharmaceutical review program in the study area. The first 12 nursing homes in which the program is implemented will be allocated to the intervention group, with the remaining nursing homes forming the control group. The comparability of the groups will be ensured in terms of nursing home characteristics (geographical location, size, organizational and healthcare features) and patient profiles (sociodemographic and clinical variables.

The intervention involves a systematic and structured review of patients’ pharmacotherapeutic treatment plans to identify problems or risks associated with their medication regimens and propose changes or improvements. This procedure is part of the standard service portfolio of the regional healthcare authority and is conducted by pharmacists from the territorial Primary Care Pharmacy Unit. The intervention is based on the protocol outlined in the document “Rational use of medicines. Basic medication management in chronic patients: Reconciliation, review, desprescription, and adherence (Departament de Salut, 2013).

The review process includes two phases. In the first phase, individual pharmacological treatment plans are reviewed to identify DRPs, which are classified into four types: indication-related, appropriateness, effectiveness, and safety issues. Indication-related DRPs include medications. Without a current indication or missing necessary medications.

Appropriateness-related DRPs assess dosage, frequency, regimen, and duration, as well as the suitability of medications based on age, renal and hepatic function, and other clinical parameters. To identify potentially inappropriate medications by age group, we used the reference “Potentially inappropriate medications for the elderly” (Servei Català de la Salut, 2020), which integrates the Beers Criteria (American Geriatrics Society Beers Criteria Update Expert Panel, 2019), STOPP-START criteria (O'Mahony et al., 2015), Priscus List (Holt et al., 2010), and EU-PIM List (Fick et al., 2015), providing justification, recommendations for change and the criteria on which these recommendations are based. Effectiveness-related DRPs assess therapeutic outcomes in relation to clinical goals and identify instances of overtreatment or the need for de-intensification based on the patient’s health status.

Safety-related DRPs include therapeutic duplications, contraindications, adverse effects, allergies, drug interactions, or insufficient laboratory monitoring.

In the second phase, pharmacists issue proposals to optimize pharmacotherapy in response to identified DRPs. Recommendations may include discontinuation, substitution, therapeutic equivalents, initiation of new treatments, dosage or frequency adjustments, or enhanced monitoring.

These recommendations are then evaluated and agreed upon by a committee composed of the responsible physicians and the pharmacist. Consensus-based proposals are subsequently discussed with the patient or their legal representative, leading to a shared decision. Recommendations may be accepted or rejected.

In the control nursing homes, pharmacological treatments will be managed following standard procedures. Typically, primary care physicians only authorize and prescribe treatments proposed by nursing home physicians, with limited involvement in ongoing medication management. However, they have access to electronic clinical decision support tools aimed at improving prescribing quality. These include the self-audit tool which detects therapeutic duplications, polypharmacy, contraindications, and inappropriate treatment durations- and the PREFASEG (Safe pharmacological prescription) module, which alerts prescribers to potential interactions, contraindications, and redundancies when initiating new therapies.

Data were collected at baseline and at 3 months using the electronic prescription module of each patient’s electronic health record. The evaluation was conducted by the pharmacist implementing the intervention, who was not blinded to the study group allocation of nursing homes and patients (Table 1).

➢ Outcome variables

Drug-Related Problems (DRPs) were quantified as total number, DRPs per patient, and the proportion of patients with at least one DRP. DRPs were classified into four categories: indication, appropriateness, effectiveness, and safety (Table 2).

Polymedication was measured as the number of medications taken concurrently by each patient and the number of polymedicated patients. Polypharmacy was defined as the chronic use of ≥10 medications (Duerden et al., 2013; Gnjidic et al., 2012). Topical treatments, eye drops, occasional treatments, and those used for acute conditions were excluded from this count. Fixed-dose combinations were counted according to the number of active ingredients. Multiple dosages of the same active ingredient were counted as one drug.

➢ Secondary variables

Sociodemographic variables such as age and sex were collected. Regarding the pharmacotherapeutic plan, the number and classification of DRPs identified (by indication, appropriateness, effectiveness, or safety) were recorded.

Clinical variables included physical comorbidity, such as the presence of chronic conditions like diabetes, cardiovascular disease, respiratory disease, dementia, and cancer. Psychiatric comorbidity included diagnoses of depression, anxiety, psychotic disorders, and substance use disorders.

Comorbidity was also quantified using the Charlson Comorbidity Index (Charlson et al., 1987), which integrates age and 19 clinical conditions to provide a summary score correlated with 1-year and 10-year survival.

To assess chronic care complexity, we recorded the number of patients identified as Complex chronic patients (PCC) or as part of the Advanced chronic care model (MACA) (Departament de Salut, 2017). PCCs are defined by clinicians as having complex clinical management needs due to multimorbidity, a polypharmacy, clinical instability, resource use, and age extremes. MACA patients are those with a limited life expectancy and palliative care needs.

Functional status was assessed using the Barthel Index (Mahoney and Barthel, 1965), which evaluates independence in activities of daily living on a scale from 0 (total dependence) to 100 (total independence), categorized as severe (0–50), moderate (51–75), or mild/no dependency (76–100).

Cognitive status was assessed using the validated Short portable mental status questionnaire (SPMSQ) by Pfeiffer (Martínez de la Iglesia et al., 2001), composed of 10 items scored from 0 to 10. Cognitive impairment was classified as: none (0–2), mild (Baena et al., 2014; Patel and Zed, 2002), moderate (Nivya et al., 2015; Zhou et al., 2018; Duerden et al., 2013), or severe (≥8).

In the intervention group, pharmacist recommendations were categorized as (Meyer-Massetti et al., 2018): drug discontinuation (Ruiz-Ramos et al., 2021), drug substitution (Baena et al., 2014), therapeutic equivalent change (Patel and Zed, 2002), treatment initiation (Nivya et al., 2015), close monitoring (Zhou et al., 2018), dose adjustment, or (Duerden et al., 2013) frequency adjustment. The number of recommendations implemented within 3 months was also recorded.

Based on prior observations and published studies, we assume that the proportion of patients with drug-related problems (DRPs) will be 50% in the control group (Vink et al., 2011; Costa et al., 2016; Garin et al., 2021). We expect to detect an absolute reduction of 10 percentage points in the prevalence of medication-related problems, from 50% in the control group to 40% in the intervention group. This difference is considered clinically meaningful, as even a modest reduction in such problems may lead to significant improvements in patient safety and care quality in the nursing home setting.

The sample size is calculated to account for the cluster design of the study, using the GRANMO calculator (https://www.datarus.eu/en/applications/granmo/). Assuming an alpha risk of 0.05 and a power of 0.80 in a two-sided test to detect a difference between proportions of 0.50 in the control group and 0.40 in the intervention group, a total of 24 clusters (12 per group) with 37 participants per cluster is required, including an estimated 10% loss to follow-up. A low intraclass correlation coefficient (ICC) of 0.001 is assumed. In the absence of published ICC estimates for this setting, we adopt a conservative value consistent with other studies involving individual-level binary outcomes with limited clustering. If the actual ICC or the number of participants per cluster differs substantially from expectations, we will conduct a sensitivity analysis to assess the potential impact on statistical power and precision.

Participants who die during the follow-up period will be considered lost to follow-up and excluded from outcome analyses. This expected attrition has been accounted for in the sample size calculation, which includes an estimated 10% loss due to mortality and other causes of dropout.

The main analyses will be by intention to treat, taking into account the patients in each group according to the initial assignment to the study groups, regardless of the compliance with the program by the patient or the responsible physicians, or any other pharmaceutical adequacy intervention that the physicians or patients in the control group may receive.

We will first describe the baseline characteristics of the sample and compare the intervention and control groups to assess baseline comparability. Although the intervention is mainly directed at the prescribing physician through recommendations or suggested changes, outcomes will be assessed at the individual patient level. We will account for potential non-independence of observations arising from patients being managed by the same physician (cluster effect).

Primary outcome variables include: number of DRPs per patient, proportion of patients with DRPs, number of medications per patient, and proportion of polymedicated patients. The effects of the intervention on dichotomous outcomes will be assessed using multilevel mixed-effects logistic regression models (cluster-adjusted), with the odds ratio (95% CI) of the intervention group versus control serving as the measure of effect. For continuous variables, we will use linear mixed-effects regression models (cluster), calculating differences between adjusted means (95% CI) between the intervention and control groups. Statistical significance will be set at p < 0.05.

This is a pragmatic clinical trial conducted under real-world clinical practice conditions. The pharmaceutical intervention under study is part of the primary care pharmaceutical services.

Patient data will be extracted from the Electronic health record by the Department of information systems. The principal investigator (PI) will work with a dataset derived from this extraction, in which patient information will be pseudonymized. Pseudonymization process will be carried out by the Department of information systems. This department will generate and send a code–patient identity correspondence document to the responsible clinician, exclusively for the purpose of facilitating the shared decision-making process. PI will not have access to the document linking patient identity to the pseudonymized codes, ensuring compliance with data protection and confidentiality standards. Portfolio and is being evaluated during its implementation process in routine clinical practice.

In all cases, it is the responsibility of the treating physician to evaluate the applicability of the recommendations generated by the medication review, based on clinical judgment and in consultation with the patient. As a safeguard against potential harm, a criterion for exclusion was that the physician considered participation potentially detrimental for the patient. Patients in the control group facilities received the pharmaceutical intervention after the study follow-up period, according to the planned implementation process.

The study was designed in accordance with the Good research practice guidelines in health sciences of the Catalan health institute (Institut Català de la Salut, 2010), the principles of the Declaration of Helsinki (2013 revision), and applicable regulations.

The protocol was reviewed and formally approved by the Clinical research ethics committee (CEIC) of IDIAP Jordi Gol (Barcelona), including the formal exemption from informed consent for patients.