Potentially Prescriptions Inappropriate (PPIs) in elderly patients in polytherapy: structured discussion on the effect of medication therapy review using evaluation criteria listed in literature on the administrative health care database

Lorella Magnani

Hospital Pharmacy, Pharmaceutical Department, Tuscany North West Health Company, Area of Massa Carrara, Italy

INTRODUCTION

In most western countries, the elderly population represents the proportion of the population that is intended to grow to a greater extent in the coming years, with significant implications on the consumption of health care resources considered the complexity physio-pathological of the elderly, affection from multimorbidity,physical/ cognitive disability and geriatric syndromes.

The medication in elderly patients is a complex activity that requires a clinical careful evaluation and constant monitoring with eventual revaluation periodic of therapy plan. For this reasons, in the last few years numerous evidences have shown an increased prevalence of “Potential Inappropriate Prescriptions (PPIs)”.1

The scientific evidences document that in the elderly ( ＞/=65 years) it is a major priority to minimize the risks resulting from the PPIs. Observational studies2,3have estimated that, over a period offive years 1/4 elderly patients are hospitalized for problems consequent to drugs given, causing more than 10%of all admissions in this population (of which the 30–35%could be avoided), that 1/3 elderly patients taking ＞ 5 drugs has experience an adverse reaction, that 44% of elderly patients discharged from the hospitals is prescribed at least one drug is not necessary.

The evidence suggests that predictive factors more strongly related to the inappropriate use of drugs are polytherapy, for effect of multimorbidity elderly population, uncritical application of guidelines in many cases inadequate and built with data from young subjects-adults affected by a single pathology (ex.the elderly ＞ 75 years with comorbidity are n’t in the clinical studies pre-marketing), an approach excessively oriented to the treatment of individual diseases (according to axiom “a drug - a disease”), the simultaneous presence of several specialists who follow the same patient without any interaction between them.These factors, together with the effects of aging on the main pharmacokinetic and pharmacodynamic parameters, increased the risk of interactions, of adverse drug reactions and use of potentially inappropriate drugs.

The Guidelines, in addition to not take account of the numerous diseases from which the elderly are affected, recommend drug regimens that may be inadequate and expose the subject to significant risks.4Also the presence of “geriatric conditions”,rarely considered in clinical trials or guidelines, which cognitive degeneration, impairment of the functional state, drops and limited waiting of life, may influence the effectiveness of the pharmacological treatment, compromising the appropriateness sometimes5;since it is not easy to estimate the “limited waiting for life”,being a parameter influenced by many variables, the accuracy of the real prognosis is key to determining whether a patient is eligible or not of a specific treatment.6Specifically, number of drugs taken,cognitive degeneration, impairment of the functional state, chronic pain, compromising the effectiveness of the communication and ability to report the symptoms related to adverse reactions from the drug, influence the adherence to therapy and directly affect the complexity of clinical management. Moreover ,the physiological disruptive of the aging process, accompanied by changes in the pharmacokinetics and pharmacodynamics parameters,7-9further complicates the complex management of the therapeutic plan rest on the risk of adverse reactions from the drug, both due doserelate, either drug-drug interaction or drug-pathology, modifying extremely the risk-benefit ratio of the pharmacological treatment,10as well as predisposing to the phenomenon of “the prescriptive cascade” (interpretation of symptoms due to complications of the polypharmacy as a new disease, adding a new drug). According to what is reported in the literature, an elderly takes from 6 to 8 drugs/day11: a polipharmacology, defined as the contemporary use of 5 or more drugs, concern the 50% of the elderly ＞ 65 years,amount to how an independent risk factor of hospitalization, institutionalisation, reduction of the functional performance, malnutrition and adverse reactions (ADR).12,13Also, the number of drugs taken is a predictive factor of poor adherence to treatment and potential interactions between drugs14: the analysis of the relationship between the number of drugs prescribed and the likelihood of potential adverse reactions due to interactions between drugs (ex.increase of one of the existing pathologies for the phenomenon of “therapeutic competition”) is an issue of great importance from the point of view of epidemiological drug and is the subject of several studies in recent years. In this regard, because only registries can provide information ,in real- life conditions, about the realationship between multimorbidity/polypharmacy/clinical outcomes (mortality, re-hospitalization, adverse events..), in Italy started REPOSI study (Registro POliterapie SIMI), in which the findings of 3-yearly runs (2008-2010-2012) suggest the promotion and implementation of multidisciplinary team approach to health care of the multimorbid elderly patients.

Given the above and considering that polytherapy is any case necessary (due to the effect of comorbidity and longer life expectancy), is unavoidable not acknowledge the impossibility, as much for clinicians as for any guideline all interactions: in this perspective the application of evaluation scientifically based criteria and information technology tools could represent a resource for to tend to prescriptive appropriateness, still a challenge for researchers, clinicians, manager, third-payers, being a complex and multidimensional concept, cannot be traced back to a single interpretation, that includes complex conditions context-dependent that must be defined as measured by specific methods. Just, a prerequisite to be implemented in a concrete process of measuring or monitoring the appropriateness is the definition of scientifically based criteria to which the evaluations and results that can be used traced back to different objectives:of quality of care, preparation of recommendations, preparation of practical support to the work of the clinician, identification of areas worthy of research.

In the end, it must also be considered that over the years, the variable costs (due to the need to contain the growing healthcare costs) have become part of the concept of appropriateness, which is therefore placed in the context of cost-effective relationship, as a result of a “decision-making process that ensures maximum benefit within the available resources”.15

Potentially Prescriptions Inappropriate (PPIs): explanation

The definition of “Potentially Inappropriate Prescription”includes:

• inappropriate use of the drug, both for the duration that dosage, both in excess and deficiency, or an excessive frequency assumption;

• contemporary use of most drugs that interact between them(drug-drug interaction) and/or with diseases of which the geriatric patient is affection (drug-disease interaction);

• low-prescription of a drug has its motivations of the age of the patient or because the patients already taking too many drugs,without revision of therapies and evaluation the relevance on the basis of the clinical state, cognitive and functional.

It is good to underline that Potentially Inappropriate drugs deserves special vigilance, but they do not necessarily have to be forbidden in all cases for all patients.

In addition to the risk of adverse reactions to drugs, the main consequences of PPIs are a lower adherence to treatment and an increase in the use of resources and services of health-care with consequent negative impact on the costs of care and assistance.Then, the “appropriate prescribing” is a priority objective in the elderly patient: in the literature it is reported that elderly tend to develop ADRs with a probability seven times greater compared to young: the prevalence of hospitalizations related to the taking of drugs presents a large heterogeneity among the different studies (mean 5–10% with peaks of up to 31%), in relation to the setting of study (all admissions or only acute admissions in the hospitals), to the population concerned (hospital complete, specific departments, population selected or certain age groups), the type of reactions/event measured (definition used to detect ADRs/AEs ), the type of data collection method(revision of medical records, spontaneous reports or searching for databases). Moreover, in the elderly in which is frequently the atypical presentation of morbid conditions, the ADRs can be difficult to diagnose and can be interpreted as a symptom of a new pathology, triggering the phenomenon of the “prescriptive cascade”.16The prescriptive cascade occurs whenever a new sign or symptom, expression of ADR/AE is interpreted as new pathology leading to the prescription of new specific drugs. The ADR can be even more difficult to discriminate when the adverse event coincides with the event already common in the population under examination or in the case in which cognitive deficits and functional condition the adherence to the therapeutic plan.16

Potentially Prescriptions Inappropriate (PPIs): evaluation criteria

The evaluation of PPIs in the elderly can be performed applying implicit or explicit outcomes based on general criteria developed by international expert groups e/o creating expert groups local for the relative contextualization.17

The main methodological approaches include:

1) Implicit criteria

Are focused on the analysis of patients (based on the evaluation of the clinical case) rather than on the drug or disease and are less easily standardizable.18

a) Appropriate Medication Index19includes ten criteria that and each prescription is classified on the basis of a final score;

√ appropriate score =1

√ marginally appropriate score =2

√ inappropriate score=3

The fields considered are: indications for use, clinical effectiveness, dose, method and drug route, drugs-drug- drug interactions,diseases interactions, costs, duplications, duration of therapy.

b) Index Lipton20includes six category of problems related drug; each category provides definitions and examples.

The fields considered are: allergies, dosage (under-or overdose), posology (frequency of use), appropriateness (lack of indications, not optimal choice), interactions between drugs,duplication.

2) Explicit criteria

Are focused on the drug or disease, can be applied directly on large databases, even in the absence of a clinical judgment and/or the knowledge of the clinical characteristics of the patient and do not consider the factors that define the quality of health care.18

a) Beers criteria21;

b) Mc Leod 1997 criteria22;

c) STOPP criteria (Screening Tool of Older Person’s Prescriptions) & START (Screening Tool to Alert doctors to Right Treatment);

d) ZAN criteria23;

e) LAROCHE criteria24;

f) NORGEP criteria25;

g) CRIME criteria26;

h) Geriatric Working Group of AIFA criteria.27

The criteria of Beers were the first set of explicit indicators of prescriptive appropriateness in elderly, processed in 1991 in the USA for the elderly institutionalised, subsequently revised and updated (last vers.2015),28applicable to patients ＞ 65 years of any setting of caring. The criteria of Beers are among the sources most frequently consulted about the safety of prescriptions in the elderly in clinical medicine geriatric, in education and in research and development of prescriptive quality indicators. The main objective of this set of indicators is to orient the doctor in the choice of the drug to prescribe to elderly, avoiding the active principles with a high risk of adverse reactions and/or suggesting carefully, without limiting the freedom prescriptive, the priorities and objectives therapeutic care, the choices and the will of the patient or family-caregiver.

Despite the various revisions, the criteria of Beers still have limitations: do not refer to the inappropriate underutilization of drugs and do not consider the attention to the use of duplicates(two drugs of the same therapeutic class used simultaneously),conditions which on the contrary take on STOPP & START criteria, for that motive should be used together.

Furthermore, all studies that have examined the usefulness of these criteria, the main objective was to evaluate the prevalence of individuals exposed to the use of the PPIs or the rate of reduction as a result of intervention education/training in different settings, therefore lack prospective studies that have examined the effectiveness of the Beers criteria on hard clinical outcomes, such as reduction of undesired effects, access to emergency services,admitted to the hospital, disability and mortality.

The STOPP & START criteria published for first time in 2008(vers.1) and updated in the 2014 (vers.2) by a group of European experts, aren’t easy to apply in daily clinical practice for the volume of information rules (114 criteria) and for different health policies.

The START criteria are a group of indicators (34) aimed at identifying potential errors of prescription omission of drugs that would be indicated for that particular patient, but not included in therapy; the criteria STOPP (80) are other sizeable group of indicators that included interactions drug-drug, drug-disease,duration and dosage.

In Italy, the Geriatric Working Group of the Regulatory Agency National –AIFA27developed a set of indicators to evaluate the quality of pharmacological prescription, selecting only those concerning pharmacological prescriptions refund by SSN (Health Service National), the prevalence of which was assessed by analyzing the data present in the National Observatory on the use of medicinal products AIFA (Osmed), relative to the Italian population with age greater than or equal to 65 years. Are not easily applied in routine clinical practice due to the volume on information and multiple rules that apply, but the develop.Subsequently, on the basis of the prevalence and availability of data on the effects of the indicator in question on the elderly national population, thirteen have been identified, and for each indicator a descriptive sheet has been prepared and reviewed by pharmacological experts.

Methods

Applications Software

Whereas normally the clinician fails to revise the prescriptions by applying the various criteria to both the respective complexity (not all software of prescription generate alert signals in cases of PPIs)and for the reason of time, the development software applications has open the real possibility of using the criteria in clinical practice.29,30For these reasons, over the years, various project have been created for the realization informatics technology (IT) tools that support the various criteria.

Examples are the SENATOR project funded by the European Commission based largely on the criteria STOPP & START31and the STRIP decision support system developed in the Netherlands32based on the criteria STOPP & START combined with the POM (Polipharmacy Optimization Method) and GIVE(Gebruik Indicatie Veiligheid Effectiviteit] criteria: in this model the pursuit of the treatment plan is monitored through medical pharmacist-patient interaction.

A very important aspect for the success of the software applications is the usability and e recent systematic review can improve the efficacy, but evidences for clinical, economic, workload and efficiency outcomes remains sparse.33

A major challenge is that any software solution would need to safely handle the complexity that characterizes elderly patients. A recent review concluded that there are validated, reliable, widely used prevention strategies in older people.34

Querying the Administrative health care date

The application of explicit criteria (ex. Beers and STOPP &START) to the administrative data base of pharmaceutical prescriptions could represent a screening too, not only to qualitatively and quantitatively asses PPIs, given immediate availability of information, but above all to create practical support for the clinician’s work by crating “adaptive database” for interactive research for specific conditions, considered the organizational variability frequently observed in clinical care activities and professional behaviour.

Making a retrospective analysis on the administrative database of pharmaceutical prescriptions using the explicit criteria chosen according to the context) it is indeed possible to estimate the prevalence of interactions drug-drug, drug-dose, drug-duration,category of PPIs and ATC (Anatomic Therapeutic Chemical classification system) class and also the cost of inappropriate drugs (ex. drugs unnecessary); furthermore, with multiple logistic regression models it is possible to determine the association(compared to/not) between ATC class detected, polipharmacy,age, sex.

The application of the selected explicit criteria to the administrative data base of pharmaceutical prescriptions, not contemplating an autonomous software, it does not elaborate output on practical advice or alert, but generates an extraction list of PPIs with patient parameters and prescribed medications,creating a practical work support to the clinician for a possible critical review (medication therapy review), also without the face-to-face with patient.

To obtain the PPIs list it is necessary to formulate a query(the proposed items are on the Appendix A) to be applied to the administrative database of pharmaceutical prescriptions: it is desirable that it be designed by a multidisciplinary team made up of clinician or geriatrician, general practitioner and pharmacist, who of the most recent literature, taking into account the context, local economic policies (SSN refund, prices ...) chooses the criteria to be applied.

The pharmacist extracts the output of the query (PPIs list) and assists the clinician in the review of the therapy plan, in particular to formulate practical advice on the favorable cost-effective option for the individual case (manual optimization)35and for bibliographic support documentation.

For the medication therapy review the prescriber can evaluate whether to use the POM (Prescribing Optimization Method)based on simple six questions36and to request, if appropriate,the advice of the geriatrician. In literature it is reported that the Geriatric evaluation and review of drug therapy have proven to be effective methods in helping prescribers to optimize the polypharmacy.36,37

In according to English General Medical Service contract the medication therapy review should be done every fifteen months for chronic therapy and anticipated each time the therapy is reviewed or dosages is changed38,39while the English National Service Framework to older people the revision should be done once a year for patients ＞ 75 years, or very six months for patients＞ 75 years taking ＞ 4 drugs.39

Type of medication therapy review

The medication review is part of the patient’s medication management can be done schematically in three ways:

• Simple: medication history

• Intermediate: medication history + prescription list (alternatively: medication history + patient interview)

• Advanced: medication history+ prescription list + patient interview

The patient interview could be useful for to evaluate the drug adherence (compliance) and to collect any adverse event /discomfort and share the optimization of the therapy plan.

CONCLUSIONS

The various implicit and explicit criteria available in the literature should neither dictate prescription protocols alone, nor serve from justification for limiting health coverage, but intended as a starting point for adjusting a subject's pharmacological regime.Indeed, it is advisable that the prescriptive choices must take into account the most recent evidence published to support or against the use of the drugs present in the various lists. The warnings and logics concerning the recommendations expressed in the criteria are as important as the recommendations themselves: respecting these nuances could help health professionals understand why the drugs are included in the lists and how the prescription approach could be adjusted accordingly.

Regardless of more or less functional software applications,more multidimensional and multidisciplinary efforts (ex. geriatric counseling) are needed to take on problems related to polypharmacy in elderly patients: the most appropriate therapeutic regimen should combine guidelines, geriatric assessment, social and economic considerations, the patient's will and should be periodically reviewed, especially as the presence of multiple comorbidities increases the risk of adverse reactions.37

Appendix A

Items (proposal) in the formulation of the query:

1. Choice of explicit criteria to use

2. Definition of possible adaptations and contextualization, considering the drug on the market, the rules of National Agency(AIFA) and European Agency (EMA) agencies introduced to promote the prescriptive appropriateness

3. Definitions of inclusion and exclusion criteria (ex. age, sex,particular pathologies…)

4. Definitions of the categories by gravity of the PPIs ( ex. to avoid always, to use in specific circumstances, to be administered with patient monitoring..)

5. Choice of method for identify drug duplications ( ex. drug same ATC classes..)

Author contributions

LM is the sole contributor/author who drafted entire manuscript and completed the final edit/proofing review of the manuscript.

Conflicts of interest

None declared.

Financial support

None.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

Open access statement

This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work noncommercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

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