Long-Term Care medicines formularies: any reasons for pharmacists’ concern?

Abstract This study aimed to characterize and compare medicines formularies (MFs) used in Long-Term Care (LTC) facilities in Portugal, and to identify the prevalence of Potentially Inappropriate Medicines (PIMs). A systematic contact with LTC facilities was undertaken in December 2021. MFs were systematized according to the Anatomical Therapeutical Chemical classification system (ATC), followed by descriptive content analysis. A structured comparison between MFs developed by public organizations and private LTC facilities was performed. After duplicate removal and exclusion of medicines not for systemic use, two explicit criteria - the Algorithm of medication review in frail older people and the EU(7)-PIM list - were employed for PIMs identification. Five MFs were obtained and assessed. The three MFs developed by private institutions covered 23% of the national LTC facilities and approximately 34% of the national total of beds. Heterogeneity was particularly high for the Alimentary tract and metabolism, Blood and blood-forming organs, Musculoskeletal system, and Respiratory system ATC groups. A PIM prevalence of 29,4% was identified. Medicines distribution between the MFs suggests the need to develop national guidelines towards harmonizing medicines usage in LTC. The prevalence of PIMs found highlights the importance of a particular optimized use of this health technology in aged sub-populations.


INTRODUCTION
Medicines are a crucial technology in healthcare systems and one of the most frequently used in Long-Term Care (Fenstemacher, 2010).Long-Term Care (LTC) comprises a range of healthcare, personal care, and other supportive services targeted to patients whose capacity for self-care is limited.In Portugal, the National Network of Long-Term Integrated Care (NNLTC) represents the country's response to the growing demand for this level of care (Ministério da Saúde and Ministério do Trabalho Solidariedade e Segurança Social, 2006;World Health Organization, 2000).Services performed by the NNLTC are delivered at patient homes and community-based services or institutional settings, with pharmacists assisting the latter framed by hospital pharmacy regulations.Supervision and monitoring of the NNLTC are under public control (Ministério da Saúde and Ministério do Trabalho Solidariedade e Segurança Social, 2006).Nonetheless, LTC teams work autonomously regarding medicines use, leading to the heterogeneity of practices.Patients assisted by the NLTIC are mainly elderly (83% are 65 years old or over), with high prevalences of multimorbidity and polypharmacy, aligned with the international LTC patients' profile (Ministério da Saúde and ACSS, 2020; Wang et al., 2018).The elderly living in LTC facilities (LTCFs) are more susceptible to experiencing Adverse Drug Events (ADEs) than noninstitutionalized elderly individuals (Kapoor et al., 2020).Potentially Inappropriate Prescribing (PIP) encompasses i) misprescribing, i.e., the prescription of a medication that could potentially lead to a significant risk of ADEs, due to Page 2/11 Braz.J. Pharm.Sci.2023;59: e22802 erroneous posology or route of administration or due to increased risk of drug-drug or drug-disease interaction; ii) underprescribing or Potential Prescribing Omission (PPO), i.e., the omission of a medication that is clinically indicated for disease treatment or prevention; and iii) overprescribing, i.e., the prescription of medications for which no clear clinical indication exists (O'connor, Gallagher, O'mahony, 2012;Rankin et al., 2018).Within the concept of misprescribing, Potentially Inappropriate Medications (PIMs) represent a set of medications with greater risk than benefit to a patient, consequently increasing the risk of ADEs and associated with poor health outcomes especially in aged populations.In addition, polypharmacy is a preponderant determinant for the higher prevalence of PIMs (Mekonnen et al., 2021).Thus, the identification of PIMs in aged sub-populations of LTC systems represents an important field of action to improve the quality of prescribing.
Over the last decades, a plethora of tools and interventions have been published in scientific literature addressing medicines optimization through improving prescribing practices (Onder et al., 2013).Tools assessing the appropriateness of prescribing can be classified as explicit (i.e., criteria-based) or implicit (i.e., judgmentbased) (Kaufmann et al., 2014).Implicit criteria require clinical expertise and data about the patient (e.g., previously unsuccessful treatment, preferences), whilst explicit criteria tools are medication-targeted and/or disease-targeted, making them more suitable for assisting medicines related decisions, including medicines formularies (MFs) development and optimization (Drenth-van Maanen et al., 2018;Kaufmann et al., 2014).
The American Society of Health-Systems Pharmacists defines a drug or medicine formulary as "a continually updated list of medications and related information, representing the clinical judgment of physicians, pharmacists, and other experts in the diagnosis, prophylaxis, or treatment of disease and promotion of health" (Tyler et al., 2008.Medicines formularies play an important role in healthcare systems.The 'Model List of Essential Medicines' was first published in 1977 by the World Health Organization and is updated every two years, highlighting the importance of medicines in healthcare systems (World Health Organization, 2022).
Medicines formularies for LTC settings will be under assessment in the present study.Medicines formularies can generically be classified as 'open' or 'closed,' and the main difference between the two types relies on the process of selection.'Open formularies' chiefly rely on prescribing orders; in contrast, 'closed formularies' are based on a previous assessment of medicines or medical devices according to clinical and economic criteria.Closed formularies are usually developed by Pharmacy and Therapeutics Committees, especially common in hospital settings (Parrish, 2018;Puigventós Latorre et al., 2011;Sofat, 2020).
Medicines formularies can positively impact clinical and economic outcomes by selecting the safest, most efficacious, and cost-effective medicines (Schiff, Cremers, Ferner, 2012).Given the importance of medicines optimization for the elderly living in LTC settings, this study aimed to characterize and compare MFs regarding the medicines selected and their suitability for aged individuals by identifying PIMs.

MATERIAL AND METHODS
The overall study design followed a statistical descriptive analysis approach, using medicines formularies in use or recommended for Long-Term Care Facilities of the Portuguese National Network of Long-Term Care.

Sampling
Medicines formularies from public institutions were retrieved from institutional websites.Contacts with LTCFs were carried out during December 2021.Direct contact with an 83-facilities LTC chain was undertaken, considering that this LTC chain's formulary was employed in 22% of the national LTCF and approximately 32% of the total national beds.The remaining 288 LTCFs were systematically contacted via email and telephone.
A sample of five MFs was obtained.Two formularies were developed by public entities -National Coordination (MF1) and a Regional Health Authority (MF2responsible for regional supervision and coordination of the NNLTC).The remaining three formularies (MF3, MF4, MF5) were developed by LTCFs' healthcare teams, covering the three types of inpatient facilities, i.e., Convalescence, Middle Term and Rehabilitation and Long-Term and Maintenance.
MF1 was released in 2011 by the National Coordination and was targeted to the entire NNLTCi.e., 371 LTCFs and 9.289 beds (inpatient settings).MF2 was released in 2016 by a Regional Health Authority; there were 19 facilities and 532 beds (inpatient settings) under the influence of MF2.MF3 was obtained from a 120-beds LTCF.MF4 was obtained from an LTCFs chain comprising 83 LTCFs and approximately 3000 beds.MF5 was obtained from a 59-beds LTCF.Excluding MFs 1 and 2, the remaining three MFs covered 23% (85/371) of the national total of LTCFs and approximately 34% (3179/9289) of the national total of beds.

Data extraction.
All medicines included in each MF were extracted to MS Excel file and coded according to the Anatomical Therapeutical Chemical (ATC) Classification system (World Health Organization, 2022).Duplicates were removed from this data set.To identify potentially inappropriate medications for elderly patients, the Algorithm of medication review in frail older people ("Poudel's criteria") (Poudel et al., 2016) and the EU(7)-PIM list explicit criteria (Renom-Guiteras, Meyer, Thürmann, 2015;Rodrigues et al., 2020) were employed.These two criteria were selected based on previous study findings published elsewhere (Gonçalves et al., 2021b).

Data comparisons
Initially, medicines formularies developed by LTCFs (MF3, MF4, MF5) were compared to a unified characterization of the national and regional formularies ('MF1 + MF2'), considering all medicines.Next, medicines not for systemic use (e.g., D -Dermatologics; S -Sensory organs) were excluded, knowing that the explicit criteria employed only refer to systemic use, followed by simple descriptive data analysis.

RESULTS
The sum of the five MFs resulted in a total of 1560 medicines.After duplicate removal, 595 different medicines were listed, of which 97 medicines were common to the five MFs (see supplemental material 1).To assess their distribution, national and regional recommendations ('MF1 + MF2') were compared to MFs autonomously developed by LTFCs (MF3, MF4, MF5).Higher rates of heterogeneity were found for the Alimentary tract and metabolism, Blood and bloodforming organs, and Musculoskeletal and Respiratory system ATC groups.Results are described next (Table I).

DISCUSSION
Despite not only targeted at aged people, the most frequent patients assisted at the National Network of Long-Term Care are the elderly, and "management of therapeutical regimen" is a common reason for admission (Ministério da Saúde and ACSS 2021).Additionally, i) the under-representation of geriatric populations in clinical trials during medicines development (van Marum, 2020); ii) the age-related pharmacokinetics and pharmacodynamics changes (McLean, Le Couteur, 2004); iii) as well as the extensively reported increase of multimorbidity, polypharmacy and pharmacotherapy complexity with aging (Nobili, Garattini, Mannucci, 2011;Nunes et al., 2016), explain the highest rates of Adverse Drug Events among the elderly.Thus, this research can improve prescribing quality in this population by addressing the identification of PIMs in geriatric sub-populations from real-world data (i.e., medicines formularies).
The reasoning for the selection of the explicit criteria employed was based on evidence adapted to the reality of the national network, that is, the "Poudel's criteria" and the EU(7)-PIM List were selected from a consensus-based study developed in the context of the NNLTC, and which also included hospital pharmacists as participants (Gonçalves et al., 2021b); the latter criteria were developed in Europe and recently adapted to the national context (Rodrigues et al., 2020).Employing "Poudel's criteria" identified 43 PIMs, while the EU(7)-PIM list identified 126 PIMs, with only 3 PIMs uniquely identified by "Poudel's criteria" (fluphenazine, methyldopa, and warfarin).This fact may indicate that, in future research, the EU(7)-PIM List can be used as the only assessment tool.Furthermore, given the commonly identified constraints in LTC pharmacy practice -e.g., lack of time and/or human resources (Gonçalves et al., 2021b) the EU(7)-PIM list seems better positioned to be used as the only assessment tool given the difficulties in using multiple tools in daily practice.The list of 129 PIMs summarised in Table II comprehends medicines whose classification as a PIM varies.Some PIMs classifications are dose-dependent (e.g., iron doses > 325mg), durationdependent (e.g., proton pump inhibitors > 8 weeks), or due to lack of proven efficacy (e.g., acarbose); thus, the prevalence of PIMs identified in our sample (29.4%) should be analyzed carefully within the patient-centered approach of medicine usage.Moreover, clinical reasoning may justify the use of some medicines classified as PIMs for specific clinical cases, such as, when medicines of first choice have proven to be ineffective, when the alternative is not available or in off-label use, a common practice in LTC and palliative care (Hagemann, Bausewein, Remi, 2019;Jackson, Jansen, Mangoni, 2012).The list of PIMs identified should flag medicines that might negatively impact patients' safety.Indeed, both the "Poudel's criteria" and the EU(7)-PIM list include reasons for considering medication as potentially inappropriate, with the EU(7)-PIM list also presenting clinical recommendations and alternatives medication and or/therapies.For these reasons, our findings can be valuable to clinical practice not only because they allow identifying PIMs, but also because the prescribing-assessment tools A systematic review identified the Alimentary tract and metabolism, the Cardiovascular system, and the Nervous system ATC groups as those more frequently associated with Drug-Related Problems or involved in medication management interventions by pharmacists in LTC settings (Gonçalves et al., 2021a).Alongside the Musculoskeletal system ATC group, the medicines included in these four ATC groups comprised the most PIMs identified in our study.This evidence can help develop tailored strategies for improved medicine usage in the NNLTC inpatient settings for prescribers, pharmacists, other healthcare professionals, and policymakers.Additionally, this work allowed us to map the most common medicines used in Long-Term Care.Formularies provide "improved patient care at decreased cost through improved selection and rational medicine use" (Management Sciences for Health and World Health Organization, 2007).Medicines formularies and Pharmacy & Therapeutic (P&T) committees seem to positively impact cost containment and influence prescribing (Godman et al., 2011;Larsen et al., 2014;de Vries et al., 2008).The national recommendations for the usage of medicines in the NNLTC are dated from 2011.This work may represent a starting point toward developing national policies to enhance medicine usage in the NNLTC, such as creating a national P&T committee for LTC and an updated national MF to address the heterogeneity identified.Through a P&T committee or similar structure, supplemented with solid guideline development methods, consensual alternatives to PIMs could be reached, increasing the clinical practice applicability of our findings.Hospital pharmacists have a broad experience in P&T committees participation, and the similarities between LTC and hospital settings are high -for instance, hospital pharmacy recommendations extensively frame Long-Term Care pharmacy practice.Therefore, hospital pharmacists can play an essential role in assisting and developing a national P&T committee and an updated national formulary.
Despite belonging to the same nationwide network, LTCFs from where formularies were sampled can assist patients with different profiles (e.g., physical rehabilitation specialized LTCFs vs. cognitive diseases specialized LTCFs).Nonetheless, the heterogeneity of the studied sample -e.g., the minimum and maximum number of medicines per formulary varies between 512 to 177, respectively; and the similarity between national recommendations and LTCF's formularies ranges from 82% to 54% -suggests the need for a national harmonization in medicines usage adjusted to this level of care.For particular ATC groups -Alimentary tract and metabolism and Respiratory system -similarities range between 58% to 68%, maximum.On the other hand, excluding sex hormones and insulins groups, the similarity between formularies is 100% for the systemic hormonal preparations.For other relevant groups -Nervous systems, Blood and blood-forming organs, and Cardiovascular system -heterogeneity is also worth mentioning, not only compared to national and regional recommendations but also among LTCF's formularies.
Medicines for Antiinfectives for systemic use -a frequent group of medicines used in LTC contexts (Jump et al., 2018) -similarities are around 100% between formularies, which can be explained by the extensive awareness campaigns and interventions on antibiotics management and consequent alignment of prescribing patterns by physicians.
According to the World Health Organization, p(ersonal)-drugs "are the drugs you have chosen to prescribe regularly, and with which you have become familiar" (de Vries et al., 1994).Baker et al. (2011) stated that the "identification of 'commonly-prescribed drugs' to support prescribing training has proved controversial".Therefore, further interventions aiming to improve prescribing practices at LTC levels through the set of medicines used daily should be delivered, taking prescribers' preferences and behaviors into account.Evidence gathered here could work as a starting point to reach a national consensus on the most suitable medicines to use in LTC patients, raise awareness of medicines used in older patients, and assist in pharmacotherapy training.
Further research should increase formularies sample enrollment and investigate relationships between the presence of pharmacists, the profile of patients assisted, formularies heterogeneity, and suitability to elderly subpopulations of the National Network of Long-Term Care.
Although the sample encompasses a substantial proportion of LTCFs and beds, an increase in MFs enrolment would better control for potential biases or confounders, considering the low rate response (out of 288 LTCFs contacted, 2 replied).Furthermore, only Portuguese lists were considered, hindering the generalization of our findings to other countries (i.e., medication market differences, different prescription profile, population).
Hospital pharmacists' experience and expertise would be of utmost importance to pursue these objectives.

TABLE I -
Medicines formularies comparison

TABLE I -
Medicines formularies comparison

TABLE II -
Potentially Inappropriate Medications

TABLE II -
Potentially Inappropriate Medications

TABLE II -
Potentially Inappropriate Medications

TABLE II -
Potentially Inappropriate Medications

TABLE II -
Potentially Inappropriate Medications