De las Salas R, Eslava-Schmalbach J, Vaca-González C, Rodríguez D, Figueras A. Development of a stepwise tool to aide primary health care professionals in the process of deprescribing in older persons. Pharmacy Practice 2020 Oct-Dec;18(4):2033. https://doi.org/10.18549/PharmPract.2020.4.2033 Original Research Development of a stepwise tool to aide primary health care professionals in the process of deprescribing in older persons Roxana DE LAS SALAS , Javier ESLAVA-SCHMALBACH , Claudia VACA-GONZÁLEZ , Dolores RODRÍGUEZ , Albert FIGUERAS . Received (first version): 13-Jul-2020 Accepted: 22-Nov-2020 Published online: 4-Dec-2020 Abstract Objective: The aim of this study was to develop and validate a stepwise tool to aid primary health care professionals in the process of deprescribing potentially inappropriate medication in older persons. Methods: We carried out a systematic review to identify previously published tools. A composite proposal of algorithm was made by Article distributed under the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International (CC BY-NC-ND 4.0) license following the steps from clinical experience to deprescribe medications. A 2-round electronic Delphi method was conducted to establish consensus. Eighteen experts from different countries (Colombia, Spain and Argentina) accepted to be part of the panel representing geriatricians, internists, endocrinologist, general practitioners, pharmacologists, clinical pharmacists, family physicians and nurses. Panel members were asked to mark a Likert Scale from 1 to 9 points (1= strongly disagree, 9= strongly agree). The content validity ratio, item-level content validity, and Fleiss’ Kappa statistics was measured to establish reliability. The same voting method was used for round 2. Results: A 7-question algorithm was proposed. Each question was part of a domain and conduct into a decision. In round 1, a consensus was not reached but statements were grouped and organized. In round 2, the tool met consensus. The inter-rater reliability was between substantial and almost perfect for questions with Kappa=0.77 (95% CI 0.60-0.93), for domains with Kappa= 0.73 (95%CI 0.60-0.86) and for decisions with Kappa= 0.97 (95%CI 0.90-1.00). Conclusions: This is a novel tool that captures and supports healthcare professionals in clinical decision-making for deprescribing potentially inappropriate medication. This includes patient’s and caregiver’s preferences about medication. This tool will help to standardize care and provide guidance on the prescribing/deprescribing process of older persons’ medications. Also, it provides a holistic way to reduce polypharmacy and inappropriate medications in clinical practice. Keywords Deprescriptions; Polypharmacy; Inappropriate Prescribing; Clinical Decision-Making; Algorithms; Pharmacists; General Practitioners; Geriatricians; Physicians, Family; Consensus; Delphi Technique; Validation Studies as Topic; Colombia INTRODUCTION be exposed to potentially inappropriate medications (PIMs).6 An older person is defined by the United Nations as “those aged 60 or 65 years or over.1 Age-related issues that need Deprescribing is defined as a "planned and supervised to be considered are changes in pharmacokinetics and process of dose reduction or interruption of medication pharmacodynamics, multiple chronic diseases, that can cause harm, that does not provide a benefit, or polypharmacy (more than four medications), cascade that is considered inappropriate".5 It is often employed as a prescription, and unnecessary or inappropriate strategy to cease medications when one of the following medication.2-5 conditions is present: Drugs cause adverse effects, do not have a current indication, are not currently in use, are used Polypharmacy is increasing in older persons, and it has irregularly in non-life-threatening conditions, or are used to been associated with increased risk of adverse drug events, treat adverse effects of other drugs.14 Deprescribing is a falls, hospitalizations, and emergency admissions.6-12 personalized process, because it takes into account the Polypharmacy is considered part of geriatric syndrome and patient’s and caregiver’s preferences and lifestyle.15 Hence, a predictor of hospitalization, and nursing home deprescribing is an essential process but sometimes a placement.13 Additionally, older persons are more likely to challenging task for clinicians. Recent tools and criteria for deprescribing have been Roxana DE LAS SALAS. BSN, MSc. Department of Pharmacy, developed to evaluate PIMs.15,16 However, conceptual tools Faculty of Sciences, National University of Colombia. Bogotá that prompt clinicians to consider, in a logical way, all (Colombia). rpdem@unal.edu.co Javier ESLAVA-SCHMALBACH. MD, MSc, PhD. Professor. relevant factors for making prescribing decisions may help Department of Public Health, Faculty of Medicine, National to minimize the number of inappropriate drugs. With our University of Colombia. Bogotá (Colombia). jheslavas@unal.edu.co proposal, health care professionals may find support on a Claudia VACA-GONZÁLEZ. Pharm, MSc. Associate professor. Department of Pharmacy, Faculty of Sciences, National University of practical approach to assist clinical decision-making in the Colombia. Bogotá (Colombia). cpvacag@unal.edu.co deprescribing process. Dolores RODRÍGUEZ. MD, PhD. Assistant professor. Department of Pharmacology, Therapeutics and Toxicology, Autonomous The Guide to Good Prescribing proposed by the World University of Barcelona. Barcelona (Spain). drficf@gmail.com Albert FIGUERAS. MD, PhD. Professor. Department of Health Organization (WHO) establishes throughout its Pharmacology, Therapeutics and Toxicology, Autonomous stages the possibility of prescribing only if necessary and University of Barcelona. Barcelona (Spain). afs@icf.uab.cat deprescribing if necessary. This indicates that 1 www.pharmacypractice.org (eISSN: 1886-3655 ISSN: 1885-642X) © Pharmacy Practice and the Authors De las Salas R, Eslava-Schmalbach J, Vaca-González C, Rodríguez D, Figueras A. Development of a stepwise tool to aide primary health care professionals in the process of deprescribing in older persons. Pharmacy Practice 2020 Oct-Dec;18(4):2033. https://doi.org/10.18549/PharmPract.2020.4.2033 prescription/deprescription is a holistic process. Therefore, expert panel discussion following the Delphi consensus the aim of this study was to develop and validate a method; and (iii) the inter-rater reliability using Fleiss’ stepwise tool to aid primary health care professionals in the Kappa. process of deprescribing PIMs in older persons. Stage 1: tools design To identify previously developed deprescribing tools, a METHODS literature search in MEDLINE (via PubMed), EMBASE, We planned three consecutive phases: (i) tool design; (ii) LILACS, SCIELO was made using the final list of PIM, and Figure 1. Algorithm for deprescribing 2 www.pharmacypractice.org (eISSN: 1886-3655 ISSN: 1885-642X) © Pharmacy Practice and the Authors De las Salas R, Eslava-Schmalbach J, Vaca-González C, Rodríguez D, Figueras A. Development of a stepwise tool to aide primary health care professionals in the process of deprescribing in older persons. Pharmacy Practice 2020 Oct-Dec;18(4):2033. https://doi.org/10.18549/PharmPract.2020.4.2033 terms such as: 3; 4 to 6; 7 to 9) to consider strong agreement and thereby to declare consensus. (("aged" OR elderly[Title/Abstract] OR older adult[Title/Abstract]) OR frail older adult[Title/Abstract]) Round 1 included 16 experts from Colombia, Spain and AND (((((("inappropriate prescribing" OR withdrawing Argentina who participated by e-mail and were given a 2- treatment[Title/Abstract]) OR over week deadline to establish whether they agree with the prescribing[Title/Abstract]) OR Inappropriate inclusion of each domain, question (item), and action Drugs[Title/Abstract]) OR deprescription[Title/Abstract]) (decision) category. After the first round, the OR Inappropriate Medications[Title/Abstract]) OR recommendations given by the experts were accepted, Inappropriate Medicines[Title/Abstract]). allowing for substantial improvement of the tool. Because the scores of the degree of agreement were distributed Articles presenting tools, algorithms, and conceptual along the Likert scale scores, it was necessary to develop a frameworks to identify PIMs were included from inception second round. to March 2020. The terms were adjusted for each of the databases. Round 2 included 18 experts and it was performed to reduce the disagreements from the first round. Both The tool design was structured following content items and rounds included feedback of the obtained results. Table 1 domain construction. From the beginning, the proposed and Table 2 show the domains (factors), the seven tool included four domains (indication, adverse drugs questions, and the actions (decisions) of the proposed tool. effects, preferences of the patient and their caregiver, The rounds were conducted via e-mail using an electronic assessment and follow up), seven questions organized by survey. the domains and five possible decisions (remove, reduce, switch, continue medication and restart medication). The Stage 3: Measurement of interrater reliability last step of the tool suggests repeating the process This phase was performed to stablish interrater reliability regularly. The tool was developed following the conceptual by measuring the content validity ratio, item-level content framework shown in Figure 1. validity, and Fleiss’ Kappa of each domain, item, and action. Stage 2: Delphi consensus method The inter-rater reliability consisted in determining Pre-consensus agreement among raters using a Likert Scale from 1 to 9 points (1=strongly disagree, 9=strongly agree). The level of The initial algorithm was proposed by five experts from precision, clarity, and comprehensibility of the tool was Spain and Colombia (two family physicians and three acceptable with a minimum of 0.7 (substantial) percent of clinical pharmacologists) as part of a pre-consensus stage. agreement, using Fleiss’ Kappa statistic.17 The degree of After constructing a merged proposal with the existing reliability was established by Fleiss’ kappa: tools, we evaluated the concordance rated for each item, domain and decision included, following an electronic Delphi consensus method. Rounds The content validity ratio (CVR) for each item was A 2-round electronic Delphi method was conducted to evaluated using a three-degree range scale (not necessary, establish consensus. A total of 20 international experts useful but not essential, and essential). The minimum were invited to participate and eighteen accepted to be acceptance ratio was 0.58, according to Lawshe modified part of the panel (five geriatricians, two internists, one by Tristán.18 Also, the content validity index was used to endocrinologist, three general practitioners, two calculate the global reliability of the tool. pharmacologists, three clinical pharmacists, one family physician, and one nurse). Panel members were asked to Statistical analysis mark a Likert Scale from 1 to 9 points (1=strongly disagree, Experts’ agreement scores were reported as medians and 9=strongly agree). It was estimated a rank scale zone (1 to ranges. Fleiss’ kappa and 95% confidence intervals (95%CI) Table 1. Level of agreement in the relevance of each domain, items Round 1 Round 2 (n=16) (n=18) Domains (factors) /Questions Median Rank Median Rank Factor 1. INDICATION - - 9 7-9 1. Is the use of the medication supported by a correct and relevant clinical indication? 9 5-9 9 9 2. Does the medication offer a real benefit to the patient according to the prognosis of life? 8 7-9 8 7-9 3. Is it the indicated dose appropriate? 8 1-9 8 8-9 4. Is there any potentially harmful interaction? 7 3-9 7 8-9 Factor 2. ADVERSE DRUGS EFFECTS - - 8.5 7-9 5. Is there any risk of adverse drug reaction that exceeds the expected benefits? 9 5-9 9 9 Factor 3. PREFERENCES OF THE PATIENT AND/OR THEIR CAREGIVER - - 8 7-9 6. Does the patient have a complaint about the use of the medication? 9 1-9 9 7-9 Factor 4. ASSESSMENT AND FOLLOW UP - - 9 7-9 7. Assess if the evolution of the disease has been exacerbated after the deprescription of the 9 3-9 9 9 medication Domains (-): Not evaluated. 3 www.pharmacypractice.org (eISSN: 1886-3655 ISSN: 1885-642X) © Pharmacy Practice and the Authors De las Salas R, Eslava-Schmalbach J, Vaca-González C, Rodríguez D, Figueras A. Development of a stepwise tool to aide primary health care professionals in the process of deprescribing in older persons. Pharmacy Practice 2020 Oct-Dec;18(4):2033. https://doi.org/10.18549/PharmPract.2020.4.2033 Table 2. Content validity for questions Useful but Items/domains Essential Not necessary CVR CVR' Kappa Interpretation not essential Factor 1 16 2 0 0.77 0.88 0.69 Substantial Q1 18 0 0 1.00 1.00 1.00 Almost perfect Q2 15 3 0 0.66 0.83 0.56 Moderate Q3 18 0 0 1.00 1.00 1.00 Almost perfect Q4 15 3 0 0.66 0.83 0.56 Moderate Factor 2 17 1 0 0.88 0.94 0.83 Almost perfect Q5 18 0 0 1.00 1.00 1.00 Almost perfect Factor 3 15 3 0 0.66 0.83 0.56 Substantial Q6 16 2 0 0.77 0.88 0.69 Substantial Factor 4 17 1 0 0.88 0.94 0.83 Almost perfect Q7 15 3 0 0.66 0.83 0.56 Moderate 0.77 95% CI Total (Ítems) 115 11 0 5.77 6.38 Substantial (0.60-0.93) Global CVI 0.82 0.91 Total (domains) 57 15 0 2.77 3.38 0.73 95% CI Substantial (0.60- 0.86) CVI global 0.69 0.84 Interpretation criteria for Kappa, using guidelines described by Landis and Koch. Poor= 0.00, slight= 0.01 – 0.20, fair= 0.21 – 0.40, moderate= 0.41 – 0.60, substantial= 0.61 – 0.80 and almost perfect= 0.81 – 1.00. CVR: content validity index. CVR’= content validity ratio. CVI: item-level content validity. were calculated after each round to evaluate reliability. The Round 2: In the second round, the values of the median level of reliability was carried out using R program version 3.6.0. were between 7 and 9 for the questions (rank= 7-9), from 8.5 to 9 (rank= 7-9) for domains, and 9 (rank= 7-9) for Ethical statement actions (Table 1). All the proposed changes were accepted. Because the rank values were between 7 and 9 in Likert The study protocol was approved by the ethics committee scale, there was a definite consensus in round 2. of the Faculty of Science of the Universidad Nacional de Colombia (ID: 06-2017), and experts were asked to consent Tool interrater reliability to take part in a two round Delphi process. In round 1, the minimum percentage of agreement for precision, clarity, and comprehensibility of the tool was RESULTS only achieved for questions 5 and 7. Fleiss’ Kappa was calculated for all items and showed that agreement was Tool design not achieved. The composite tools that were collated from 14 existing In round 2, the minimum percentage of agreement for tools generated an initial list of 8 questions. Figure 1 shows precision, clarity, and comprehensibility of the tool was seven questions included in the proposed tool and these achieved for all questions (items), factors (domains) and are grouped according to the different domains and actions. Fleiss’ Kappa was calculated for all items and it actions. The proposal was obtained for a 2-round electronic indicated that agreement was accomplished. Delphi method. Each question had two possible answers; yes or no. Supplement 3 displays the algorithm with All items had a content validity index (CVR) higher than footnotes for each question in order to extend some 0.58, meaning all items were accepted. The content validity considerations for each one. obtained strength of agreement between moderate, substantial, and almost perfect by the experts, which Delphi consensus method allows affirming that the tool was sufficient. The global CVI Round 1: In the first round, the median (x̃) values were of the instrument was 0.82 and CVI values for items were between 7 and 9 for questions and from 8 to 9 for actions between 0.66 and 1.00. respectively (Table 1). There was no consensus on Fleiss’ Kappa was 0.77 (95%CI 0.60 to 0.93) for items; 0.73 questions 3, 4, 5, 6, and 7; 1 and 5 had a relative consensus, (95%CI 0.60 to 0.86) for domains, and 0.97 (95%CI 0.90 to and 2 was the only one that had agreement in round 1. 1.00) for actions. According to Landis and Koch, the The actions (decisions) did not show a definitive consensus achieved interrater reliability was between substantial and in round 1. “Cease” had consensus in this round (x̃= 9; 7-9). almost perfect (Table 2 and Table 3). “Reduce”, “cease/reduce/switch”, “switch” (rank= 1-9) and “continue medication” did not show consensus (rank= 3-9). DISCUSSION “Repeat the process regularly” had a relative consensus (rank= 5-9). We propose a tool specifically designed to deprescribe PIMs in older patients. This tool incorporates a step by step As a result of this round, “cease/reduce/switch” had a systematic approach for identifying, assessing and, strong recommendation from experts to be deleted and withdrawing said medications on an individual basis. modified to “cease”. “Reduce” was suggested to change to Although current tools give us an opportunity to take out a “adjust” (related to the dose). comprehensive list of potentially inappropriate and high- 4 www.pharmacypractice.org (eISSN: 1886-3655 ISSN: 1885-642X) © Pharmacy Practice and the Authors De las Salas R, Eslava-Schmalbach J, Vaca-González C, Rodríguez D, Figueras A. Development of a stepwise tool to aide primary health care professionals in the process of deprescribing in older persons. Pharmacy Practice 2020 Oct-Dec;18(4):2033. https://doi.org/10.18549/PharmPract.2020.4.2033 Table 3. Content validity for actions Useful but Not Actions Essential CVR CVR' Kappa Interpretation not essential necessary CEASE 18 0 0 1.00 1.00 1.00 Almost perfect ADJUST 18 0 0 1.00 1.00 1.00 Almost perfect SWITCH 18 0 0 1.00 1.00 1.00 Almost perfect CONTINUE 18 0 0 1.00 1.00 1.00 Almost perfect RESTART 17 1 0 0.88 0.94 0.83 Almost perfect 0.97 TOTAL 89 1 0 5.13 5.06 Almost perfect 95%CI (0.90-1.00) Global CVI 0.73 0.72 Interpretation criteria for Kappa, using guidelines described by Landis and Koch. Poor=0.00, slight=0.01- 0.20, fair=0.21- 0.40, moderate=0.41- 0.60, substantial=0.61-0.80 and almost perfect=0.81-1.00. CVR: content validity ratio. CVI: item-level content validity. risk medications, further factors of inappropriate In the last domain, we include the assessment and follow prescribing, such as incorrect clinical indication, no benefit, up of the overall process. If the healthcare professional presence of drug interaction (drug-drug, drug-disease, finds that the patient’s conditions have been exacerbated drug-food or drug-herb), adverse drug reactions or any after deprescription, the tool proposes to restart complaint by the patient or caregiver about the use of medication. However, it is important to evaluate that medications, might be missed. additional factors might be the causes of patient's exacerbation. Hence, it is necessary to monitor the In the first domain, we included questions that assess the patient’s condition in order to establish if any other indication of medication. The first question consists in additional factors could potentially explain it. Therefore, we checking if there is a relevant clinical indication for the expect that the probability of restarting the prescription is medication. Thus, this is maybe the most crucial question going to be lower because our first two questions are of the tool because if the answer is "no", there is no reason strong. The last step of the process is to repeat the process to keep the medication, and the action is to cease it. Then, regularly, considering that patient conditions may change the health provider does not need to follow the next throughout time. question. It means that the different items are mutually exclusive. The second question evaluates the current The Delphi method was implemented to assess the validity benefit of the therapy according to the patient's life and reliability of the tool. The domains, questions, and prognosis. If the answer is no, the action is to cease the actions were established through a pre-consensus and two medication. The next item asks if the indicated dose is discussion rounds with international experts. It is to be appropriate. Additionally, the last question in this domain is noted that consensus methods have been extensively used to validate other well-known tools.20,21 In general, the to establish if there is any potentially harmful interaction. proposed tool was very well accepted by the experts in the McKean et al. established a tool for identifying and first round. The adjustments made aimed at improving the discontinuing unnecessary medications in the inpatient precision, clarity, and comprehensibility of the tool. setting, in order to reduce medication burden that only Therefore, we proposed to change these measures to cease asks about indications, benefits and adverse drug because if there is a severe adverse drug reaction, the reactions.16 decision would be to withdraw the medication. All the In the second domain, we consider ceasing medications adjustments made in round one allowed for a definitive with adverse drug effects that overwhelm the possible consensus in round two. Experts noted that our proposal benefits. This item intends to identify adverse drug events included all the steps performed in real clinical practice. that might cause negative health outcomes such as falls, We acknowledge that the utility of the tool in clinical hospitalizations, emergency admissions, or conditions practice needs to be evaluated, but our expert’s validation caused by medicines.8-12 McKean et al. and Garfinkel et al. process confirms that it has all the elements of the real also consider this aspect in their proposals.16,19 Adverse process to make decisions about older persons’ drug effects are definitively a critical issue in medications. We conducted a robust process for prescribing/deprescribing process. Hence our proposal also establishing validity and reliability, which means our includes this aspect. proposal includes all the domains and questions that the In the third domain, we incorporate a question to ask about deprescribing process has. Prescribers and health care the preferences of patients or caregivers. If there is any providers are welcome to use the tool and provide complaint about the use of the medication, the suggestion feedback about their perceptions on its utility. Future work is to switch to another. Hardy & Hilmer consider that will be focused on tool validation by assessing its deprescribing should be undertaken as a team approach, performance in real clinical settings. not only by involving medical doctor(s), pharmacists and The application of the tool could be limited by the nursing staff, but also patient/caregivers.15 Our proposed multiplicity of prescribers who evaluate patients tool is the only one that follows an expert validation (cardiologists, pulmonologists, internists, neurologists, process and considers the patient’s/caregiver’s suggestions endocrinologists, geriatricians, among others), leading to and complaints as possible and valid reasons for excessive prescription and making deprescribing difficult. deprescribing. To overcome these difficulties, we suggest all medical specialists to use the tool as a support on decision making about older adult medication. The proposed tool could 5 www.pharmacypractice.org (eISSN: 1886-3655 ISSN: 1885-642X) © Pharmacy Practice and the Authors De las Salas R, Eslava-Schmalbach J, Vaca-González C, Rodríguez D, Figueras A. Development of a stepwise tool to aide primary health care professionals in the process of deprescribing in older persons. Pharmacy Practice 2020 Oct-Dec;18(4):2033. https://doi.org/10.18549/PharmPract.2020.4.2033 support medication reconciliation and improve patient contributions and participation in the validation process. health outcomes. This work was supported by the Office of Management and Academic Development of the Universidad del Norte. RD is The Canadian D-PRESCRIBE trial is an example of using a doctoral scholar at Universidad Nacional de Colombia. deprescribing tools for specific medications such as benzodiazepines, z-drugs, first-generation antihistamines, Panel members: Miguel Oswaldo Cadena-Sanabria MD, glyburide, and NSAIDs; these tools being used by ACGG (Asociación colombiana de geriatría y gerontología); pharmacists and demonstrating the benefits of Robinson Cuadros MD, ACGG; Jordi Espinàs MD Primary deprescribing strategies.22 This study showed that Health Care Center Santa Eugènia de Berga Institut Català deprescribing promoted a higher number of interruptions de la Salut (Spain); Guadalupe María Henao RN, MSc, of inappropriate prescriptions, when compared to routine Department of Nursing at Universidad de Caldas; Juan care after 6 months, the study’s length; meaning that the Erviti-López PharmD, Navarra Health Department (Spain); main outcome evaluated was the reduction of the Catalina Torres-Espinosa MD, ACGG, Universidad Nacional pharmacological burden caused by these specific de Colombia; Oscar Gómez-Cárdenas, MD, GP, MSc(c), medications. However, the results on the benefits Universidad Nacional de Colombia; Hernán Santiago-Perea emanated from a reduction in hospitalizations, falls, MD, MSc, Universidad Nacional de Córdoba (Argentina), adverse effects, among others, remain to be measured.22 Oscar Andia MD, GP, Colombian medical federation; Jorge Enrique Machado-Alba MD, PhD, Universidad Tecnológica CONCLUSIONS de Pereira, Diego Andrés Chavarro-Carvajal MD, ACGG, Universidad Javeriana; Rodrigo Heredia MD, ACGG; Juan The proposed tool systematically captures the process of Felipe Meneses, José Julián López G, Mauricio Alvarez MD, deprescribing performed in clinical practice. It also gives an IM, Intellectus Medical Center, San Ignacio Hospital; Jorge approximation of the complex pharmacotherapy in older López MD, ACGG, Universidad Nacional de Colombia; people and reflects the domains, questions, and decisions Mauren Ospina Pharm, Audifarma Pharmacy; and Adriana of deprescribing. The tool includes the preferences and complaints that patients and their caregivers have about Betancourt-Rodríguez Pharm, Universidad Nacional de medications. This aspect allows the identification of Colombia. possible reasons for deprescribing that might only be known by patients or caregivers, which often are dismissed CONFLICT OF INTEREST or unheard by the practitioners and could potentially allow for a more tailored approach aimed at improving health None of the authors has any conflict of interest. outcomes. The tool is useful to support the discontinuation of PIMs in older persons and improve their health FUNDING outcomes. The deprescribing tool was supported by Colciencias contract (110177758303 CT-792-2018) and Doctoral ACKNOWLEDGMENTS Fellowship Program 647-2015. The authors thank the Universidad Nacional de Colombia and the entire collaborating group for their valuable References 1. United Nations. World population ageing 2019: Highlights. 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