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Adherence to COPD treatment: Myth and reality
Accepted Manuscript Adherence to COPD treatment: Myth and reality Paola Rogliani, Josuel Ora, Ermanno Puxeddu, Maria Gabriella Matera, Mario Cazzola PII:
S0954-6111(17)30173-7
DOI:
10.1016/j.rmed.2017.06.007
Reference:
YRMED 5183
To appear in:
Respiratory Medicine
Received Date: 1 March 2017 Revised Date:
31 May 2017
Accepted Date: 12 June 2017
Please cite this article as: Rogliani P, Ora J, Puxeddu E, Matera MG, Cazzola M, Adherence to COPD treatment: Myth and reality, Respiratory Medicine (2017), doi: 10.1016/j.rmed.2017.06.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ACCEPTED MANUSCRIPT Review article
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Adherence to COPD treatment: myth and reality
Paola Rogliani1,2, Josuel Ora2, Ermanno Puxeddu1,2, Maria Gabriella Matera3, Mario
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Cazzola1
1
Vergata, Rome, Italy 2
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Chair of Respiratory Medicine, Department of Systems Medicine, University of Rome Tor
Division of Respiratory Medicine, Department of Internal Medicine, University Hospital Tor
Vergata, Rome, Italy 3
Chair of Pharmacology, Department of Experimental Medicine, University of Campania
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“Luigi Vanvitelli”, Naples, Italy
Correspondence: Prof. Mario Cazzola, Dipartimento di Medicina dei Sistemi, Università di Tor
Vergata,
Via
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Roma
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[email protected]
Montpellier
1,
00133
Rome,
Italy,
e-mail
2
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Abstract COPD is a chronic disease in which effective management requires long-term adherence to pharmacotherapies but the level of medication adherence is very low and this has a negative influence on outcomes. There are several approaches to detect non-adherence, such as pharmacy refill methods, electronic monitoring, and self-report measures, to
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assessing adherence of patients with COPD, but they are all burdened with important limitations. Medication adherence in COPD is multifactorial and is affected by patients (health beliefs, cognitive abilities, self-efficacy, comorbidities, psychological profile, conscientiousness), physicians (method of administration, dosing regimen, polypharmacy,
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side effects), and society (patient-prescriber relationship, social support, access to medication, device training, follow-up). Patient-health care professional, especially patient-
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physician or patient-pharmacist communication is central to optimizing patient adherence. However, the most realistic approach is to keep in mind that non-adherence is always possible, indeed, probable.
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Key words: Adherence, COPD, taxonomy.
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1. Introduction COPD is a chronic disease in which effective management requires long-term adherence to pharmacotherapies [1]. A US study that investigated the association of COPD maintenance medication adherence with hospitalization and health care spending documented that patients with higher adherence to prescribed regimens experienced
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fewer hospitalizations and lower spending outcomes than those who exhibited lower adherence behaviours [2]. Conversely, decreasing medication adherence was associated with increasing COPD symptoms, hospitalizations, mortality, and high cost of medication, and also with irregular clinic attendance [3]. Risk of hospitalization or death increased by
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58 and 40%, respectively, in COPD patients who were non-adherent to combination of an inhaled corticosteroid (ICS) and a long-acting β2-agonist (LABAs) [4]. A large Italian
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population-based cohort study assessed the impact of adherence to inhaled drug use on 5-year survival in COPD using healthcare linked datasets (hospitalization, mortality, drugs) [5]. The continuous use of combined LABA/ICS was associated with a higher 5-year survival in comparison with regular use of LABAs in moderate-to-severe COPD patients, and, in turn, patients under regular use of LABAs had a higher 5-year survival than those occasionally treated with LABA/ICS.
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Deviation from the prescribed dosing regimens is a fixed constant in the interaction between physician and patient. Hippocrates was the first to note that numerous patients did not take their prescribed medicines, and many later complained because the treatment
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did not help [6].
Nowadays, it is surprising that the level of medication adherence in COPD patients is very
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low, lower than that recorded for other diseases [7], although the progressive nature of COPD and the negative effects of poor adherence to prescribed treatment are well known. Regrettably, there are difficulties in understanding the real dimension of the problem and the causes that determine it because it problematic to compare the results of different studies carried out. Actually, over the years there have been substantial changes in the terminology used to describe the deviations from prescribed dosing regimens and this ha made it difficult any attempt to connecting various studies.
2. The ascertaining barriers to compliance taxonomy
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ACCEPTED MANUSCRIPT The publication of the Ascertaining Barriers to Compliance (ABC) taxonomy, which was an initiative of the European Union to standardize adherence-related terminology for clinical and research use, marked an important step forward in the standardization and future development of adherence research [6]. The ABC taxonomy proposed that the definitive target of adherence management is “to
order to maximize benefit and minimize the risk of harm” [6].
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achieve and maintain the best use, by patients, of appropriately prescribed medicines in
The new notional basis for a transparent taxonomy relies on three elements, with a strong distinction between processes that describe actions through established routines and the
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disciplines that study those processes [6]. ‘Adherence to medications’ is the process by which patients take their medications as prescribed. It has three components: initiation
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when the patient takes the first dose of a prescribed medication, implementation that is defined as the extent to which a patient’s actual dosing corresponds to the prescribed dosing regimen, from initiation until the last dose is taken, and discontinuation that marks the end of therapy, when the next dose to be taken is omitted and no more doses are taken thereafter. Persistence is the length of time between initiation and the last dose, which immediately precedes discontinuation. ‘Management of adherence’ is the process of
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monitoring and supporting patients' adherence to medications by health care systems, providers, patients, and their social networks. ‘Adherence-related sciences’ includes the disciplines that seek understanding of the causes or consequences of differences between
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the prescribed (i.e. intended) and actual exposures to medicines. Having identified in the 'adherence-related sciences' one of the cornerstones in the issue of adherence to medication is definitely very important because, as already highlighted by
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the World Health Organization (WHO) in 2003, adherence is a multidimensional phenomenon determined by the interplay of five sets of factors, termed “dimensions”, of which patient-related factors are just one determinant [8]. Among the causes for the lack of success of chronic treatments, the WHO mentioned economical and social factors, the medical team assisting the patient, the health system, the characteristics of the disease, the treatment itself, and factors related to the patient. Therefore, the common belief that patients are solely responsible for taking their treatment is misleading and most often reflects a misunderstanding of how other factors affect people’s behaviour and capacity to adhere to their treatment [8].
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ACCEPTED MANUSCRIPT Being focused on patient adherence in COPD, Bourbeau and Bartlett [9] agreed that also in COPD adherence is multifactorial and highlighted that patients (health beliefs, cognitive abilities, self-efficacy, comorbidities, psychological profile, conscientiousness), physicians (method of administration, dosing regimen, polypharmacy, side effects), and society (patient-prescriber relationship, social support, access to medication, device training,
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follow-up) affect it. The interplay between patients and physicians is definitely crucial, with mutual important influences, while the role of the society is an element that often authoritatively affects this interplay and is scarcely influenced by the wishes and needs of individual patients or individual physicians (Figure 1).
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3. Approaches to assessing adherence of patients with COPD
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A key question is how to detect non-adherence that can take many forms: failure to fill prescriptions (primary non-adherence) or overuse, underuse or alteration of schedule or doses of medication (secondary non-adherence). In outpatient clinical settings, there is a need for a valid, reliable, cost-effective tool that is accepted by both health care providers and patients. There are several approaches (Table 1), such as pharmacy refill methods, electronic monitoring, and self-report measures, to assessing adherence of patients with
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COPD, but they are all burdened with important limitations [10]. The method that probably is the most scientifically sound is to measure drug level a drug or its metabolite in blood or urine, or a biological marker that is a nontoxic, stable, and easily detected compound added to the drug formulation in blood to confirm the intake. However, this approach is
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expensive and invasive and also reflects many factors that can result in pharmacokinetic
variations. Furthermore, blood or urine drug levels cannot quantify the manner in which the
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patient has taken the medication or detect fluctuations in compliance between clinic visits. Alternatively, and much more simply, adherence can be measured as the percentage of doses taken/doses prescribed. It is easy to use and inexpensive. However, it only assesses whether the correct number of pills have been removed and does not provide information on dose timing. Furthermore, the patients can switch medicines between bottles/boxes and may even discard pills before visits in order to appear to be following the regimen Although electronic monitors have been referred to as the “gold standard” for adherence measurement because they provide accurate and reliable records of dosage, they are expensive, subject to malfunction and cannot confirm ingestion. Furthermore, the patients
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ACCEPTED MANUSCRIPT may open the container and not take the medication, take the wrong amount of medication or take multiple doses out of the container at the same time (or place multiple doses in another container). Canister weighing is relatively simple and easy to implement. However, it is not reliable because if a patient deliberately actuates his/her inhaler multiple times consecutively over
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a short period of time even immediately prior to the visit, this can wrongly suggest optimal adherence.
Analysis of pharmacy records provides evidence of drug refill patterns but cannot assess ingestion or pattern of use and ‘dose dumping’ remains undetectable. Furthermore, refill
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records are limited in that they may be missing information, are restricted in the types of adherence that can be assessed (e.g., interdose intervals cannot be calculated), and may
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be too troublesome for providers to incorporate into practice.
It is also possible to indirectly measure adherence by using self-reported (questionnaires) adherence methods (Table 2). Barnestein-Fonseca et al. [10] have suggested employing the Haynes and Sackett method (self-reported assessment of adherence), the MorinskyGreen test (attitude towards treatment) and the Batalla test (the patients’ understanding of their illness). The Haynes and Sackett method is a patient interview. Patients are asked
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whether they ever miss their pills and, if so, they must state their current prescriptions and the average number of tablets missed per month. Adherence is then measured by computing the number of pills that they have taken during the previous month divided by
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the total number of pills they were expected to take. The Morinsky-Green test consists of 4 closed questions (1. Do you ever forget to take your inhaled medication?; 2. Are you careless at times about taking your inhaled medication?; 3. When you feel better, do you
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sometimes stop taking your inhaled medication?; 4. Sometimes, if you feel worse when you take the inhaled medication, do you stop taking it?), with a wrong answer to any question indicating a non-compliant patient. The Batalla test was originally developed to verify the knowledge of patients about blood pressure and later was used as a predictor of adherence and knowledge of individuals about other diseases. There is good adherence when the COPD patient is able to answer correctly these three questions: 1. Is COPD a lifelong disease?; 2. Can you control this disease by quitting smoking and/or with medication?; 3. Mention one or more organs that can get damaged by COPD.
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ACCEPTED MANUSCRIPT It has been reported that although the prevalence of treatment adherence changes over time, the combination of the attitude towards treatment (Morisky-Green test) and the patient’s knowledge of COPD (Batalla test) is the best approach to test self-reported adherence [9]. However, it must be pointed out that self-reporting is frequently inaccurate and has moderate reliability (25%-67%) when compared against more objectives
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measures of adherence such as canister weight and electronic monitoring [11]. Moreover, systematic investigation can be both burdensome and inconvenient from a patient-doctor relationship point of view.
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4. How patients can affect adherence in COPD
Patient-related factors represent his/her resources, knowledge, attitudes, beliefs,
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perceptions and expectations [8]. Low expectation of the medication, presence of comorbid illnesses, depressed mood, increased age, current smoking, and lack of confidence in the provider are the most consistent independent predictors of low adherence [4].
Patient views on medication effectiveness are more powerful predictors of reported adherence than socio-demographic factors or other clinical factors [12]. Actually, a study
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that investigated the effect of a range of demographic and psychosocial variables on medication adherence in COPD patients managed in a secondary care setting, showed that those subjects who felt that their medications were totally or mostly effective were more likely to report adherence to their medications, as well as participants with higher
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level of confidence in their ability to manage or avoid breathing difficulty while participating in certain activities. On the other side, patients who had lower knowledge about COPD
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medications and disease management were more likely to be in the low-adherence group. Nevertheless, the analysis of data from the Copenhagen General Population Study, a prospective cohort study, documented that higher education was associated with decreased adherence to maintenance medication [13]. A possible explanation could be that highly educated individuals may choose to rely more on their own judgment and, consequently, adjust dosages to perceived symptoms rather than simply follow a fixeddosage regime [13]. There are several other factors on a patient level that can influence the degree of medication adherence. In German COPD patients, female gender was associated with
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ACCEPTED MANUSCRIPT earlier discontinuation of long-acting bronchodilator therapy, whereas older age was associated with a lower risk of discontinuation [14]. In the Copenhagen General Population Study, use of, and adherence to, maintenance medication for COPD was low although they increased with the progressive severity of COPD as defined by GOLD stage [13]. On the contrary, the presence of comorbidities did not seem to affect medication adherence of
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COPD patients [15]. There is evidence that patients that are likely to be non-adherent (or adherent) to maintenance COPD medication are also likely to be non-adherent (or adherent) to COPD medications. This finding indicates that adherence to medications may be impacted by factors that do not change regardless of disease or medication type but
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reasonably is influenced by aspects of patient-related considerations (forgetfulness, suboptimal health knowledge, etc.), although also the health system (lack of coordinated health care, access restrictions, etc.) and socioeconomic status (education, income, etc.)
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can play a role [15].
The psychological profile is a key driver in determining adherence to medications also in COPD patients. Among a US representative sample of Medicare beneficiaries who filled COPD maintenance medications, depression diagnosis, which occurs commonly in COPD patients, was associated with lower COPD maintenance medication adherence [16].
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Although there is a significant association between anxiety, depression, or both conditions and impaired health-related quality of life (HRQoL), an improved HRQoL may surprisingly be a trigger for non-adherence in patients with COPD [17]. It has been suggested that the relationship between medication adherence and HRQoL may be dual. The impact of
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medication adherence on HRQoL might be a consequence of the effectiveness of therapy and the negative effects (i.e., adverse events, daily life limitation of therapy, social stigma)
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that it can generate. HRQoL might also influence the patterns of patients’ drug use, since an increased HRQoL might trigger non-adherence. However, the dynamics between adherence and HRQoL might differ over time, and the negative effects of medication nonadherence might become dominant on the long term [17].
5. How physicians can affect adherence in COPD The physician can affect adherence in COPD with his/her prescription because medication class to be administered, method of administration, dosing regimen, polypharmacy, and also the possible occurrence of adverse events can all influence compliance to prescribed therapy, although patient preference must always be considered a crucial factor when
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ACCEPTED MANUSCRIPT choosing drug, method of administration, and dosing regimen. Since factors associated with long-term adherence to medications for treatment of COPD likely differ by medication class, clinicians should inquire separately about the use of inhaled therapies and that potential interventions may need to be medication-specific [18]. Patient perception of clinician expertise in lung disease seems to be the factor most highly
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associated with long-term adherence to therapies. This is a potentially modifiable factor. Actually, therapy adherence to inhalation medication for the treatment of COPD seems to be related to the medication prescribed, although it is inversely associated to lung function [19]. Apparently, adherence to treatment with long-acting muscarinic antagonists (LAMAs)
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is the highest, mainly if they are dosed once-daily, whereas the opinion of improving adherence by using combined preparations does not seem to be supported by the
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evidence.
These findings have been confirmed by the evaluation of data included in a large German claims dataset. It showed that agent-specific non-persistence rates were: 58.5% for LABA, 47.9% for LAMA, 78.0% for ICS, and 69.4% for single-device LABA/ICS combination treatment [14]. In comparison to patients who started long-term therapy with a LABA, patients initially receiving a LAMA were less likely to show non-persistence, whereas
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patients who were initiated on ICS therapy or on an ICS/LABA fixed-dose combination had a higher risk of earlier non-persistence. Results of non-adherence were very similar to the non-persistence analysis.
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Several factors are related to ICSs and LAMAs adherence, but a clear profile of the patient who shows underuse or overuse cannot yet be outlined [20]. A better lung function,
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expressed as a higher FEV1/VC ratio, predisposes patients to decreased use of their medication, whereas a worse lung function predisposes them to overuse. Overuse is strongly associated also with anxiety for dyspnea and current smoking. It has been suggested that the incorporation of once-daily dose administration is an important strategy to improve adherence [21]. In effect, it was documented that COPD patients who initiated treatment with once-daily dosing had significantly higher adherence than other daily dosing frequencies [1]. Better treatment adherence was found to yield reductions in healthcare resource utilization and cost [1]. However, a retrospective cohort study that used data from the UK Optimum Patient Care Research Database (OPCRD) revealed that approximately half of the patients in each cohort indicated once-daily
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ACCEPTED MANUSCRIPT preference, one-quarter were unsure, and one-quarter did not prefer once-daily therapy [22]. The preference for once-daily controller medication was significantly associated with poor adherence and higher concerns about medication. Contrary to what happens in patients with asthma in whom good control and low self-perceived controller medication need were associated with once-daily preference, in COPD patients, a high self-perceived
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need for controller medication was associated with once-daily preference. It has been suggested that this happens because COPD symptoms are progressive and often debilitating, and affected patients tend to have multiple co-morbidities which may mean they are already on a complex cocktail of drugs and are keen to simplify their treatment
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regimen where possible [22].
Nevertheless, a study performed in an area with a centralized management system of
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pharmacological prescriptions and aimed to assess the degree of adherence for oncedaily and twice-daily regimens for administrating LAMAs, confirmed that adherence to treatment with LAMAs is very high, irrespective of the molecules or inhalation device, but did not find that patients who used twice-daily medication had a lower adherence [23]. In any case, given the time course of COPD, often physicians switch their patients to generic inhaled drugs to reduce costs. Switching from one device to another, if not
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accompanied by appropriate training for the patient, can be associated with poor clinical outcomes and increased use of health care resources [24]. Additionally, clinician’s confidence about a patient’s adherence to one class of medication should not be used as a proxy for adherence to other medications; rather, clinicians should inquire about
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adherence to each drug separately [25]. In fact, among patients with COPD, past adherence to one class of inhaled medication strongly predicts future adherence to the
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same class of medication, but only weakly predicts adherence to other classes. The method of administration can affect the level of drug adherence in COPD. At least in Japan, the adherence levels to inhaled agents were significantly poorer than that to oral medications [26]. This may be associated with local behaviors or differences in the health care system but poor adherence to only inhaled, not oral, medicines may be associated with the complexity of device usage. There is solid evidence that in COPD, adherence to inhalation medication is device-related [27]. Overuse is most pronounced for devices without a dose counter, devices with the ability to load a dosage without actual inhalation, or devices lacking feedback of correct
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ACCEPTED MANUSCRIPT inhalation. The design of the device seems to be related to underuse and overuse of inhaled medication. However, apparently there is no impact of inhaler device (multipledose versus single-dose inhalers) on COPD patients’ persistence, at least with LABAs. In fact, in a Dutch retrospective observational cohort study, persistence between users of multiple-dose and single-dose inhalers did not significantly differ [28].
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A Spanish cross-sectional multicentre study has shown that patients with COPD are more adhering to inhaled drugs than patients with asthma. Only being younger than 50 years of age and active working status were risk factors for non-adherence in the multivariate analysis, while having asthma remained in the limits of the significance [29]. In any case,
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non-adherence in patients with COPD is frequently unwitting, while that of asthma is most often erratic and deliberate.
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Older age coupled with memory loss and impaired cognitive levels lowers adherence to medications, in particular to inhalation therapy [30]. In particular, a recent prospective observational study of adherence to a regularly prescribed LABA/ICS combination inhaler by patients with COPD following discharge from hospital reported that the patient’s cognitive status may affect the patient’s ability to remember both when and how to use the inhaler [31]. Patients with poor executive functioning often display a “knowing–doing
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discrepancy.” Although they can report specific instructions, they cannot translate these into specific behavioural and motor plans and activity. Hence, abnormalities in the executive and memory domain may influence adherence through poor recall of inhaler
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technique and not remembering to use their inhaler [31]. Mastering the technique required to successfully utilize an inhaled medication delivery device is a challenging problem in the elderly, and improper technique is very common,
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even in patients who have received detailed instruction in their use [30]. In fact, physical and cognitive changes, the presence of arthritis or joint pain and also neuromuscular conditions like Parkinson’s disease or complications after stroke contribute to the difficulties that some elderly patients have with handheld inhalers [32]. In these patients, the ability to generate sufficient inspiratory flow across a dry powder inhaler (DPI) is compromised, irrespective of the presence of COPD [32], although there is evidence that lung function makes a contribution to technique errors even in those with good attempted adherence. For many patients, particularly those experiencing increased hyperinflation, it may not be possible to generate sufficient airflow for effective inhalation, and this leads to
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ACCEPTED MANUSCRIPT ineffective drug delivery [31]. The elderly may also find it difficult to actuate a pressurised metered-dose inhaler (pMDI) device [32]. All these things can adversely affect medication adherence in elderly patients. In order to overcome such disadvantages, and also to improve the adherence, aged people can use
could consider nebulizers [32].
6. How society can affect adherence in COPD
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the breath-actuated MDI that is easier to use than the pMDI or DPI. Alternatively, they
Frequently, health care systems create barriers to adherence by limiting access to health
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care, using a restricted formulary, switching to a different formulary, and having prohibitively high costs for drugs, co-payments, or both [33].
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Socioeconomic status is an intriguing factor in the search for determinants of populationlevel non-adherence to COPD because of its associations with economic, social, and education-related factors. Indeed, all these factors may affect regular medication use [8]. Socioeconomic factors that may affect adherence include poverty, illiteracy, low educational achievement, unemployment, insufficient social support, transportation issues, excessive medication and treatment costs, and environmental factors [34]. Unemployed,
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low-income patients, immigrants, and patients living alone are all at a higher risk of poor adherence to or, even, non-use of inhaled COPD maintenance medications [35]. Caregivers, especially spouses, may improve adherence in COPD. A study that aimed to
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evaluate the association between caregiver presence and adherence to medical recommendations among COPD patients showed that, compared with the “no caregiver”
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group, antihypertensive medications adherence was higher in the “spousal caregiver” and “non-spousal caregiver” groups, whereas LABA adherence was higher in the “spousal caregiver” group [36]. Patients in the “spousal caregiver” group had fewer current smokers compared with the “no caregiver” and “non-spousal caregiver”. Greater involvement of spousal caregivers likely translates into closer monitoring and a greater influence on patient behaviours, perhaps explaining why patients with spousal caregivers performed the best in all three categories. Minorities are consistently less adherent than general population [37]. This may be secondary to drug-related issues. Language barriers and cultural beliefs should be explored further to better understand their role in adherence.
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7. Methods to improve medication adherence in COPD Patient-health care professional, especially patient-physician or patient-pharmacist, communication is central to optimizing patient adherence. Building trust and developing skills for successful patient-provider communications require time, effort, knowledge, and practice [38]. However, the most often expressed barrier to improving patient-provider
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communication is inadequate time [38]. Taking extra time with those on multiple medications, where adherence is lower, is indispensable to guarantee patients understand the importance of not treating one condition at the detriment of another [37].
There is solid evidence that the impact of patients’ perceived burden of therapy on
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adherence might be modified by a better understanding of therapy, and consequently education may help reduce interruptions of COPD therapy [39]. Interestingly, education of
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patients, along with better co-ordination of care, showed significant improvements on COPD patients’ adherence [40] as well as fewer hospitalisations [41]. Also community pharmacists can have a positive and cost-effective impact in the management of COPD in relation to medication adherence and inhalation technique education, which in turn can decrease medication wastage, hospital admissions and
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severe COPD exacerbations [42]. However, the role of community pharmacists is still not fully studied or recognized, thus there is a clear need for more research. However, a 3 month randomized clinical trial (PHARMACOP trial) conducted in 170 community pharmacies throughout Belgium to assess the effectiveness of a protocol-based
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pharmaceutical care programme in patients with COPD showed that both primary outcomes, i.e. inhalation technique and medication adherence, were significantly improved
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more in the intervention group than in the control group [43]. A cost-effectiveness analysis of this trial documented that improving inhaler adherence in community pharmacies is a cost-saving strategy compared with usual care [44]. No standard intervention exists to improve adherence. However, it is likely that a multifactorial intervention focuses on motivation, knowledge and skilled inhalation technique (COPD information, dose reminders, audio-visual material, motivational aspects and training in inhalation techniques) is an effective approach to improving the therapeutic adherence in COPD patients [45]. In any case, adherence requires a behavioural change, an aspect that is related to individual interests and expectations, meaning that patients must be managed individually. Furthermore, the intervention is complex and time-
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ACCEPTED MANUSCRIPT consuming [45]. It has been highlighted that success of the ABC taxonomy within COPD needs a focus on unmet research through consistent use (and clear documentation of use) of the proposed terminology and recognized evaluation measures [46]. However, it must be interpreted and applied in the context of the specific characteristics of COPD, in which the inhaled route of
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therapy delivery is central, in particular, for its potential capacity to affect all steps of the adherence pathway negatively. In any case, producing strong research evidence requires careful selection of the best existing valuation approaches for the peculiar aspect of adherence and particular research question under consideration and clear reporting of the
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research question(s), valuation method(s), results and specific implications, and relevant context.
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Although more research is needed into the most effective approaches for optimizing medication adherence in patients, mainly seniors, with COPD, there are a number of practical opportunities for health care practitioners to intervene to support medication adherence [47]. In effect, there is a need to investigate the specific attitudes toward medication use and the adherence behaviours of seniors with COPD, develop interventions that tackle the adherence barriers specific to older patients (e.g., cognition,
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polypharmacy, and immobility), identify methods for ongoing inhaler technique support outside the professional health care environment, evaluate the role of multiple inhaler types prescribing on medication adherence and that of electronic monitors and reminders for missed doses in elderly patients with COPD. Furthermore, it is important to evaluate
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the role of secondary care experiences on medication adherence (i.e., direct-to-ward versus. to ward via the emergency room). These are all things that can be done
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immediately and do not require more than the will and time to make them. Likely, the most realistic approach is to keep in mind that non-adherence is always possible and probable. Thus, one has to remember C. Everett Koop, a former Surgeon General of the USA, who put into words something that is evident, but very frequently forgotten “Drugs do not work in patients who do not take them”. However, since adherence can be broken down not only at the initiation or persistence stage, but also, and mainly at the implementation stage, it is always imperative to consider that no drugs exert maximal effects unless patients take them as prescribed.
Conflict of interest
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ACCEPTED MANUSCRIPT All authors declare no conflicts of interest regarding the publication of this manuscript.
Funding This article did not receive any specific grant from funding agencies in the public,
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commercial, or not-for-profit sectors.
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14. Mueller S, Wilke T, Bechtel B, Punekar YS, Mitzner K, Virchow JC. Non-persistence and non-adherence to long-acting COPD medication therapy: A retrospective cohort study based on a large German claims dataset. Respir Med. 2017;122:1-11. 15. Dhamane AD, Schwab P, Hopson S, Moretz C, Annavarapu S, Burslem K, Renda A, Kaila S. Association between adherence to medications for COPD and medications for
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16. Qian J, Simoni-Wastila L, Rattinger GB, Zuckerman IH, Lehmann S, Wei YJ, Stuart B. Association between depression and maintenance medication adherence among
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17. Ágh T, Dömötör P, Bártfai Z, Inotai A, Fujsz E, Mészáros Á. Relationship Between Medication Adherence and Health-Related Quality of Life in Subjects With COPD: A Systematic Review. Respir Care. 2015;60(2):297-303. 18. Cecere LM, Slatore CG, Uman JE, Evans LE, Udris EM, Bryson CL, Au DH. Adherence to long-acting inhaled therapies among patients with chronic obstructive pulmonary disease (COPD). COPD. 2012;9(3):251-8. 19. Koehorst-ter Huurne K, Movig K, van der Valk P, van der Palen J, Brusse-Keizer M. Differences in Adherence to Common Inhaled Medications in COPD. COPD. 2015;12(6):643-8.
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ACCEPTED MANUSCRIPT 20. Koehorst-Ter Huurne K, Kort S, van der Palen J, van Beurden WJ, Movig KL, van der Valk P, Brusse-Keizer M. Quality of life and adherence to inhaled corticosteroids and tiotropium in COPD are related. Int J Chron Obstruct Pulmon Dis. 2016;11:1679-88. 21. Bjerg A, Lundbäck B, Lötvall J. The future of combining inhaled drugs for COPD. Curr Opin Pharmacol 2012;12(3):252-5.
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22. Price D, Lee AJ, Sims EJ, Kemp L, Hillyer EV, Chisholm A, von Ziegenweidt J, Williams A. Characteristics of patients preferring once-daily controller therapy for asthma and COPD: a retrospective cohort study. Prim Care Respir J. 2013;22(2):1618.
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23. Izquierdo JL, Paredero JM, Piedra R. Relevance of dosage in adherence to treatment with long-acting anticholinergics in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2016;11:289-93.
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24. Braido F, Lavorini F, Blasi F, Baiardini I, Canonica GW. Switching treatments in COPD: implications for costs and treatment adherence. Int J Chron Obstruct Pulmon Dis. 2015;10:2601-8.
25. Huetsch JC, Uman JE, Udris EM, Au DH. Predictors of adherence to inhaled medications among Veterans with COPD. J Gen Intern Med. 2012;27(11):1506-12.
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26. Imamura Y, Kawayama T, Kinoshita T, Sakazaki Y, Yoshida M, Takahashi K, Fujii K, Ando M, Hoshino T, Iwanaga T, Kohrogi H. Poor pharmacological adherence to inhaled medicines compared with oral medicines in Japanese patients with asthma and
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10.1016/j.alit.2016.10.008.
27. Koehorst-ter Huurne K, Movig K, van der Valk P, van der Palen J, Brusse-Keizer M.
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The influence of type of inhalation device on adherence of COPD patients to inhaled medication. Expert Opin Drug Deliv. 2016;13(4):469-75. 28. van Boven JF, van Raaij JJ, van der Galiën R, Postma MJ, van der Molen T, Dekhuijzen PN, Vegter S. Impact of multiple-dose versus single-dose inhaler devices on COPD patients' persistence with long-acting β2-agonists: a dispensing database analysis. NPJ Prim Care Respir Med. 2014;24:14069. 29. Plaza V, López-Viña A, Entrenas LM, Fernández-Rodríguez C, Melero C, Pérez-Llano L, Gutiérrez-Pereyra F, Tarragona E, Palomino R, Cosio BG. Differences in Adherence and Non-Adherence Behaviour Patterns to Inhaler Devices Between COPD and Asthma Patients. COPD. 2016;13(5):547-54.
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ACCEPTED MANUSCRIPT 30. Hanania NA, Sharma G, Sharafkhaneh A. COPD in the elderly patient. Semin Respir Crit Care Med. 2010;31(5):596-606. 31. Sulaiman I, Cushen B, Greene G, Seheult J, Seow D, Rawat F, MacHale E, Mokoka M, Moran CN, Sartini Bhreathnach A, MacHale P, Tappuni S, Deering B, Jackson M, McCarthy H, Mellon L, Doyle F, Boland F, Reilly RB, Costello RW. Objective
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assessment of adherence to inhalers by patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2017;195(10):1333-43.
32. Cazzola M, Rogliani P. Inhaled medication: which device for which patient? ERS Monogr. 2015;69:213-23.
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33. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353(5):48797.
34. Blackstock FC, ZuWallack R, Nici L, Lareau SC. Why Don’t Our COPD Patients Listen
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to Us? The Enigma of Nonadherence. Ann Am Thorac Soc. 2016;13(3):317-23. 35. Tøttenborg SS, Lange P, Johnsen SP, Nielsen H, Ingebrigtsen TS, Thomsen RW. Socioeconomic inequalities in adherence to inhaled maintenance medications and clinical prognosis of COPD. Respir Med. 2016;119:160-7.
36. Trivedi RB, Bryson CL, Udris E, Au DH. The influence of informal caregivers on
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adherence in COPD patients. Ann Behav Med. 2012;44(1):66-72. 37. Rolnick SJ, Pawloski PA, Hedblom BD, Asche SE, Bruzek RJ. Patient Characteristics Associated with Medication Adherence. Clin Med Res. 2013;11(2):54-65. 38. American College of Preventive Medicine. Medication Adherence Clinical Reference.
27, 2017.
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39. van Grunsven PM, van Schayck CP, van Deuveren M, van Herwaarden CL, Akkermans RP, van Weel C. Compliance during long-term treatment with fluticasone propionate in subjects with early signs of asthma or chronic obstructive pulmonary disease (COPD): results of the Detection, Intervention, and Monitoring Program of COPD and Asthma (DIMCA) Study. J Asthma. 2000;37(3):225-34. 40. Garcia-Aymerich J, Hernandez C, Alonso A, Casas A, Rodriguez-Roisin R, Anto JM, Roca J. Effects of an integrated care intervention on risk factors of COPD readmission. Respir Med. 2007;101(7):1462-9. 41. Casas A, Troosters T, Garcia-Aymerich J, Roca J, Hernández C, Alonso A, del Pozo F, de Toledo P, Antó JM, Rodríguez-Roisín R, Decramer M. Integrated care prevents hospitalisations for exacerbations in COPD patients. Eur Respir J. 2006;28(1):123-30.
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ACCEPTED MANUSCRIPT 42. Hesso I, Gebara SN, Kayyali R. Impact of community pharmacists in COPD management: Inhalation technique and medication adherence. Respir Med. 2016;118:22-30. 43. Tommelein E, Mehuys E, Van Hees T, Adriaens E, Van Bortel L, Christiaens T, Van Tongelen I, Remon JP, Boussery K, Brusselle G. Effectiveness of pharmaceutical care
controlled trial. Br J Clin Pharmacol. 2014;77(5):756-66.
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44. van Boven JF, Tommelein E, Boussery K, Mehuys E, Vegter S, Brusselle GG, Ruttenvan Mölken MP, Postma MJ. Improving inhaler adherence in patients with chronic
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obstructive pulmonary disease: a cost-effectiveness analysis. Respir Res. 2014;15:66. 45. Leiva-Fernández J, Leiva-Fernández F, García-Ruiz A, Prados-Torres D, BarnesteinFonseca P. Efficacy of a multifactorial intervention on therapeutic adherence in
trial. BMC Pulm Med. 2014;14:70.
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patients with chronic obstructive pulmonary disease (COPD): a randomized controlled
46. Vrijens B, Dima AL, Van Ganse E, van Boven JF, Eakin MN, Foster JM, de Bruin M, Chisholm A, Price D. What We Mean When We Talk About Adherence in Respiratory Medicine. J Allergy Clin Immunol Pract. 2016;4(5):802-12.
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47. Costello RW, Foster JM, Grigg J, Eakin MN, Canonica W, Yunus F, Ryan D. The Seven Stages of Man: The Role of Developmental Stage on Medication Adherence in
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Respiratory Diseases. J Allergy Clin Immunol Pract. 2016;4(5):813-20.
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ACCEPTED MANUSCRIPT Table 1 - Methods to measure adherence in COPD Advantages It is the most scientifically sound
Adherence measured as the percentage of doses taken/doses prescribed
It is easy to use and inexpensive
Electronic monitors
They provide accurate and reliable records of dosage
Disadvantages It is expensive and invasive and also reflects many factors that can result in pharmacokinetic variations. Furthermore, blood or urine drug levels cannot quantify the manner in which the patient has taken the medication or detect fluctuations in compliance between clinic visits. It only assesses whether the correct number of pills have been removed and does not provide information on dose timing. Furthermore, the patients can switch medicines between bottles/boxes and may even discard pills before visits in order to appear to be following the regimen They are expensive, subject to malfunction and cannot confirm ingestion. Furthermore, the patients may open the container and not take the medication, take the wrong amount of medication or take multiple doses out of the container at the same time (or place multiple doses in another container). It is not reliable because intentional activation of the device multiple times consecutively over a short period of time even immediately prior to the visit can wrongly suggest optimal adherence It cannot assess ingestion or pattern of use and ‘dose dumping’ remains undetectable. Furthermore,
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Method Biochemical evaluation of drug level to confirm the intake
Canister weighing
It is relatively simple and easy to implement
Analysis of pharmacy records
It provides evidence of drug refill patterns
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refill records are limited in that they may be missing information, are restricted in the types of adherence that can be assessed (e.g., interdose intervals cannot be calculated), and may be too troublesome for providers to incorporate into practice.
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ACCEPTED MANUSCRIPT Tabella 2 - Self-reported adherence methods Patient interviews, with specific questions regarding the accuracy •
Haynes and Sackett method (HST) (self-reported assessment of adherence). – Patients asked whether they ever miss their pills and, if so, to state their
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current prescriptions and the average number of tablets missed per month. Standardized, validated, adherence specific questionnaires. •
Morinsky Green test (MGT) (attitude towards treatment).
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– Good adherence to be when the patient is able to answer these four questions suitably
Do you ever forget to take your inhaled medication?
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Are you careless at times about taking your inhaled medication?
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When you feel better, do you sometimes stop taking your inhaled medication?
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•
Sometimes, if you feel worse when you take the inhaled medication, do you stop taking it?
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Batalla test (BT) (the patients’ understanding of their illness). – Good adherence to be when the patient is able to answer these three questions suitably
Is COPD a lifelong disease?
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Can you control this disease by quitting smoking and/or with
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medication?
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Mention one or more organs that can get damaged by COPD.
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•
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ACCEPTED MANUSCRIPT Figure 1 - Patients, physicians and society influence patient maintenance medication
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adherence in COPD
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Highlights The level of medication adherence in COPD patients is very low.
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Approaches to assess adherence of COPD are burdened with important limitations.
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Patient views on therapy effectiveness are powerful predictors of reported adherence.
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The physician can affect adherence in COPD with his/her prescription.
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In COPD, adherence to inhalation medication is device-related.
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S0954-6111(17)30173-7
DOI:
10.1016/j.rmed.2017.06.007
Reference:
YRMED 5183
To appear in:
Respiratory Medicine
Received Date: 1 March 2017 Revised Date:
31 May 2017
Accepted Date: 12 June 2017
Please cite this article as: Rogliani P, Ora J, Puxeddu E, Matera MG, Cazzola M, Adherence to COPD treatment: Myth and reality, Respiratory Medicine (2017), doi: 10.1016/j.rmed.2017.06.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ACCEPTED MANUSCRIPT Review article
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Adherence to COPD treatment: myth and reality
Paola Rogliani1,2, Josuel Ora2, Ermanno Puxeddu1,2, Maria Gabriella Matera3, Mario
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Cazzola1
1
Vergata, Rome, Italy 2
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Chair of Respiratory Medicine, Department of Systems Medicine, University of Rome Tor
Division of Respiratory Medicine, Department of Internal Medicine, University Hospital Tor
Vergata, Rome, Italy 3
Chair of Pharmacology, Department of Experimental Medicine, University of Campania
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“Luigi Vanvitelli”, Naples, Italy
Correspondence: Prof. Mario Cazzola, Dipartimento di Medicina dei Sistemi, Università di Tor
Vergata,
Via
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Roma
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[email protected]
Montpellier
1,
00133
Rome,
Italy,
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Abstract COPD is a chronic disease in which effective management requires long-term adherence to pharmacotherapies but the level of medication adherence is very low and this has a negative influence on outcomes. There are several approaches to detect non-adherence, such as pharmacy refill methods, electronic monitoring, and self-report measures, to
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assessing adherence of patients with COPD, but they are all burdened with important limitations. Medication adherence in COPD is multifactorial and is affected by patients (health beliefs, cognitive abilities, self-efficacy, comorbidities, psychological profile, conscientiousness), physicians (method of administration, dosing regimen, polypharmacy,
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side effects), and society (patient-prescriber relationship, social support, access to medication, device training, follow-up). Patient-health care professional, especially patient-
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physician or patient-pharmacist communication is central to optimizing patient adherence. However, the most realistic approach is to keep in mind that non-adherence is always possible, indeed, probable.
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Key words: Adherence, COPD, taxonomy.
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1. Introduction COPD is a chronic disease in which effective management requires long-term adherence to pharmacotherapies [1]. A US study that investigated the association of COPD maintenance medication adherence with hospitalization and health care spending documented that patients with higher adherence to prescribed regimens experienced
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fewer hospitalizations and lower spending outcomes than those who exhibited lower adherence behaviours [2]. Conversely, decreasing medication adherence was associated with increasing COPD symptoms, hospitalizations, mortality, and high cost of medication, and also with irregular clinic attendance [3]. Risk of hospitalization or death increased by
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58 and 40%, respectively, in COPD patients who were non-adherent to combination of an inhaled corticosteroid (ICS) and a long-acting β2-agonist (LABAs) [4]. A large Italian
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population-based cohort study assessed the impact of adherence to inhaled drug use on 5-year survival in COPD using healthcare linked datasets (hospitalization, mortality, drugs) [5]. The continuous use of combined LABA/ICS was associated with a higher 5-year survival in comparison with regular use of LABAs in moderate-to-severe COPD patients, and, in turn, patients under regular use of LABAs had a higher 5-year survival than those occasionally treated with LABA/ICS.
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Deviation from the prescribed dosing regimens is a fixed constant in the interaction between physician and patient. Hippocrates was the first to note that numerous patients did not take their prescribed medicines, and many later complained because the treatment
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did not help [6].
Nowadays, it is surprising that the level of medication adherence in COPD patients is very
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low, lower than that recorded for other diseases [7], although the progressive nature of COPD and the negative effects of poor adherence to prescribed treatment are well known. Regrettably, there are difficulties in understanding the real dimension of the problem and the causes that determine it because it problematic to compare the results of different studies carried out. Actually, over the years there have been substantial changes in the terminology used to describe the deviations from prescribed dosing regimens and this ha made it difficult any attempt to connecting various studies.
2. The ascertaining barriers to compliance taxonomy
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ACCEPTED MANUSCRIPT The publication of the Ascertaining Barriers to Compliance (ABC) taxonomy, which was an initiative of the European Union to standardize adherence-related terminology for clinical and research use, marked an important step forward in the standardization and future development of adherence research [6]. The ABC taxonomy proposed that the definitive target of adherence management is “to
order to maximize benefit and minimize the risk of harm” [6].
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achieve and maintain the best use, by patients, of appropriately prescribed medicines in
The new notional basis for a transparent taxonomy relies on three elements, with a strong distinction between processes that describe actions through established routines and the
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disciplines that study those processes [6]. ‘Adherence to medications’ is the process by which patients take their medications as prescribed. It has three components: initiation
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when the patient takes the first dose of a prescribed medication, implementation that is defined as the extent to which a patient’s actual dosing corresponds to the prescribed dosing regimen, from initiation until the last dose is taken, and discontinuation that marks the end of therapy, when the next dose to be taken is omitted and no more doses are taken thereafter. Persistence is the length of time between initiation and the last dose, which immediately precedes discontinuation. ‘Management of adherence’ is the process of
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monitoring and supporting patients' adherence to medications by health care systems, providers, patients, and their social networks. ‘Adherence-related sciences’ includes the disciplines that seek understanding of the causes or consequences of differences between
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the prescribed (i.e. intended) and actual exposures to medicines. Having identified in the 'adherence-related sciences' one of the cornerstones in the issue of adherence to medication is definitely very important because, as already highlighted by
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the World Health Organization (WHO) in 2003, adherence is a multidimensional phenomenon determined by the interplay of five sets of factors, termed “dimensions”, of which patient-related factors are just one determinant [8]. Among the causes for the lack of success of chronic treatments, the WHO mentioned economical and social factors, the medical team assisting the patient, the health system, the characteristics of the disease, the treatment itself, and factors related to the patient. Therefore, the common belief that patients are solely responsible for taking their treatment is misleading and most often reflects a misunderstanding of how other factors affect people’s behaviour and capacity to adhere to their treatment [8].
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ACCEPTED MANUSCRIPT Being focused on patient adherence in COPD, Bourbeau and Bartlett [9] agreed that also in COPD adherence is multifactorial and highlighted that patients (health beliefs, cognitive abilities, self-efficacy, comorbidities, psychological profile, conscientiousness), physicians (method of administration, dosing regimen, polypharmacy, side effects), and society (patient-prescriber relationship, social support, access to medication, device training,
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follow-up) affect it. The interplay between patients and physicians is definitely crucial, with mutual important influences, while the role of the society is an element that often authoritatively affects this interplay and is scarcely influenced by the wishes and needs of individual patients or individual physicians (Figure 1).
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3. Approaches to assessing adherence of patients with COPD
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A key question is how to detect non-adherence that can take many forms: failure to fill prescriptions (primary non-adherence) or overuse, underuse or alteration of schedule or doses of medication (secondary non-adherence). In outpatient clinical settings, there is a need for a valid, reliable, cost-effective tool that is accepted by both health care providers and patients. There are several approaches (Table 1), such as pharmacy refill methods, electronic monitoring, and self-report measures, to assessing adherence of patients with
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COPD, but they are all burdened with important limitations [10]. The method that probably is the most scientifically sound is to measure drug level a drug or its metabolite in blood or urine, or a biological marker that is a nontoxic, stable, and easily detected compound added to the drug formulation in blood to confirm the intake. However, this approach is
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expensive and invasive and also reflects many factors that can result in pharmacokinetic
variations. Furthermore, blood or urine drug levels cannot quantify the manner in which the
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patient has taken the medication or detect fluctuations in compliance between clinic visits. Alternatively, and much more simply, adherence can be measured as the percentage of doses taken/doses prescribed. It is easy to use and inexpensive. However, it only assesses whether the correct number of pills have been removed and does not provide information on dose timing. Furthermore, the patients can switch medicines between bottles/boxes and may even discard pills before visits in order to appear to be following the regimen Although electronic monitors have been referred to as the “gold standard” for adherence measurement because they provide accurate and reliable records of dosage, they are expensive, subject to malfunction and cannot confirm ingestion. Furthermore, the patients
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ACCEPTED MANUSCRIPT may open the container and not take the medication, take the wrong amount of medication or take multiple doses out of the container at the same time (or place multiple doses in another container). Canister weighing is relatively simple and easy to implement. However, it is not reliable because if a patient deliberately actuates his/her inhaler multiple times consecutively over
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a short period of time even immediately prior to the visit, this can wrongly suggest optimal adherence.
Analysis of pharmacy records provides evidence of drug refill patterns but cannot assess ingestion or pattern of use and ‘dose dumping’ remains undetectable. Furthermore, refill
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records are limited in that they may be missing information, are restricted in the types of adherence that can be assessed (e.g., interdose intervals cannot be calculated), and may
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be too troublesome for providers to incorporate into practice.
It is also possible to indirectly measure adherence by using self-reported (questionnaires) adherence methods (Table 2). Barnestein-Fonseca et al. [10] have suggested employing the Haynes and Sackett method (self-reported assessment of adherence), the MorinskyGreen test (attitude towards treatment) and the Batalla test (the patients’ understanding of their illness). The Haynes and Sackett method is a patient interview. Patients are asked
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whether they ever miss their pills and, if so, they must state their current prescriptions and the average number of tablets missed per month. Adherence is then measured by computing the number of pills that they have taken during the previous month divided by
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the total number of pills they were expected to take. The Morinsky-Green test consists of 4 closed questions (1. Do you ever forget to take your inhaled medication?; 2. Are you careless at times about taking your inhaled medication?; 3. When you feel better, do you
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sometimes stop taking your inhaled medication?; 4. Sometimes, if you feel worse when you take the inhaled medication, do you stop taking it?), with a wrong answer to any question indicating a non-compliant patient. The Batalla test was originally developed to verify the knowledge of patients about blood pressure and later was used as a predictor of adherence and knowledge of individuals about other diseases. There is good adherence when the COPD patient is able to answer correctly these three questions: 1. Is COPD a lifelong disease?; 2. Can you control this disease by quitting smoking and/or with medication?; 3. Mention one or more organs that can get damaged by COPD.
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measures of adherence such as canister weight and electronic monitoring [11]. Moreover, systematic investigation can be both burdensome and inconvenient from a patient-doctor relationship point of view.
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4. How patients can affect adherence in COPD
Patient-related factors represent his/her resources, knowledge, attitudes, beliefs,
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perceptions and expectations [8]. Low expectation of the medication, presence of comorbid illnesses, depressed mood, increased age, current smoking, and lack of confidence in the provider are the most consistent independent predictors of low adherence [4].
Patient views on medication effectiveness are more powerful predictors of reported adherence than socio-demographic factors or other clinical factors [12]. Actually, a study
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that investigated the effect of a range of demographic and psychosocial variables on medication adherence in COPD patients managed in a secondary care setting, showed that those subjects who felt that their medications were totally or mostly effective were more likely to report adherence to their medications, as well as participants with higher
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level of confidence in their ability to manage or avoid breathing difficulty while participating in certain activities. On the other side, patients who had lower knowledge about COPD
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medications and disease management were more likely to be in the low-adherence group. Nevertheless, the analysis of data from the Copenhagen General Population Study, a prospective cohort study, documented that higher education was associated with decreased adherence to maintenance medication [13]. A possible explanation could be that highly educated individuals may choose to rely more on their own judgment and, consequently, adjust dosages to perceived symptoms rather than simply follow a fixeddosage regime [13]. There are several other factors on a patient level that can influence the degree of medication adherence. In German COPD patients, female gender was associated with
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ACCEPTED MANUSCRIPT earlier discontinuation of long-acting bronchodilator therapy, whereas older age was associated with a lower risk of discontinuation [14]. In the Copenhagen General Population Study, use of, and adherence to, maintenance medication for COPD was low although they increased with the progressive severity of COPD as defined by GOLD stage [13]. On the contrary, the presence of comorbidities did not seem to affect medication adherence of
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COPD patients [15]. There is evidence that patients that are likely to be non-adherent (or adherent) to maintenance COPD medication are also likely to be non-adherent (or adherent) to COPD medications. This finding indicates that adherence to medications may be impacted by factors that do not change regardless of disease or medication type but
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reasonably is influenced by aspects of patient-related considerations (forgetfulness, suboptimal health knowledge, etc.), although also the health system (lack of coordinated health care, access restrictions, etc.) and socioeconomic status (education, income, etc.)
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can play a role [15].
The psychological profile is a key driver in determining adherence to medications also in COPD patients. Among a US representative sample of Medicare beneficiaries who filled COPD maintenance medications, depression diagnosis, which occurs commonly in COPD patients, was associated with lower COPD maintenance medication adherence [16].
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Although there is a significant association between anxiety, depression, or both conditions and impaired health-related quality of life (HRQoL), an improved HRQoL may surprisingly be a trigger for non-adherence in patients with COPD [17]. It has been suggested that the relationship between medication adherence and HRQoL may be dual. The impact of
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medication adherence on HRQoL might be a consequence of the effectiveness of therapy and the negative effects (i.e., adverse events, daily life limitation of therapy, social stigma)
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that it can generate. HRQoL might also influence the patterns of patients’ drug use, since an increased HRQoL might trigger non-adherence. However, the dynamics between adherence and HRQoL might differ over time, and the negative effects of medication nonadherence might become dominant on the long term [17].
5. How physicians can affect adherence in COPD The physician can affect adherence in COPD with his/her prescription because medication class to be administered, method of administration, dosing regimen, polypharmacy, and also the possible occurrence of adverse events can all influence compliance to prescribed therapy, although patient preference must always be considered a crucial factor when
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ACCEPTED MANUSCRIPT choosing drug, method of administration, and dosing regimen. Since factors associated with long-term adherence to medications for treatment of COPD likely differ by medication class, clinicians should inquire separately about the use of inhaled therapies and that potential interventions may need to be medication-specific [18]. Patient perception of clinician expertise in lung disease seems to be the factor most highly
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associated with long-term adherence to therapies. This is a potentially modifiable factor. Actually, therapy adherence to inhalation medication for the treatment of COPD seems to be related to the medication prescribed, although it is inversely associated to lung function [19]. Apparently, adherence to treatment with long-acting muscarinic antagonists (LAMAs)
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is the highest, mainly if they are dosed once-daily, whereas the opinion of improving adherence by using combined preparations does not seem to be supported by the
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evidence.
These findings have been confirmed by the evaluation of data included in a large German claims dataset. It showed that agent-specific non-persistence rates were: 58.5% for LABA, 47.9% for LAMA, 78.0% for ICS, and 69.4% for single-device LABA/ICS combination treatment [14]. In comparison to patients who started long-term therapy with a LABA, patients initially receiving a LAMA were less likely to show non-persistence, whereas
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patients who were initiated on ICS therapy or on an ICS/LABA fixed-dose combination had a higher risk of earlier non-persistence. Results of non-adherence were very similar to the non-persistence analysis.
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Several factors are related to ICSs and LAMAs adherence, but a clear profile of the patient who shows underuse or overuse cannot yet be outlined [20]. A better lung function,
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expressed as a higher FEV1/VC ratio, predisposes patients to decreased use of their medication, whereas a worse lung function predisposes them to overuse. Overuse is strongly associated also with anxiety for dyspnea and current smoking. It has been suggested that the incorporation of once-daily dose administration is an important strategy to improve adherence [21]. In effect, it was documented that COPD patients who initiated treatment with once-daily dosing had significantly higher adherence than other daily dosing frequencies [1]. Better treatment adherence was found to yield reductions in healthcare resource utilization and cost [1]. However, a retrospective cohort study that used data from the UK Optimum Patient Care Research Database (OPCRD) revealed that approximately half of the patients in each cohort indicated once-daily
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ACCEPTED MANUSCRIPT preference, one-quarter were unsure, and one-quarter did not prefer once-daily therapy [22]. The preference for once-daily controller medication was significantly associated with poor adherence and higher concerns about medication. Contrary to what happens in patients with asthma in whom good control and low self-perceived controller medication need were associated with once-daily preference, in COPD patients, a high self-perceived
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need for controller medication was associated with once-daily preference. It has been suggested that this happens because COPD symptoms are progressive and often debilitating, and affected patients tend to have multiple co-morbidities which may mean they are already on a complex cocktail of drugs and are keen to simplify their treatment
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regimen where possible [22].
Nevertheless, a study performed in an area with a centralized management system of
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pharmacological prescriptions and aimed to assess the degree of adherence for oncedaily and twice-daily regimens for administrating LAMAs, confirmed that adherence to treatment with LAMAs is very high, irrespective of the molecules or inhalation device, but did not find that patients who used twice-daily medication had a lower adherence [23]. In any case, given the time course of COPD, often physicians switch their patients to generic inhaled drugs to reduce costs. Switching from one device to another, if not
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accompanied by appropriate training for the patient, can be associated with poor clinical outcomes and increased use of health care resources [24]. Additionally, clinician’s confidence about a patient’s adherence to one class of medication should not be used as a proxy for adherence to other medications; rather, clinicians should inquire about
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adherence to each drug separately [25]. In fact, among patients with COPD, past adherence to one class of inhaled medication strongly predicts future adherence to the
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same class of medication, but only weakly predicts adherence to other classes. The method of administration can affect the level of drug adherence in COPD. At least in Japan, the adherence levels to inhaled agents were significantly poorer than that to oral medications [26]. This may be associated with local behaviors or differences in the health care system but poor adherence to only inhaled, not oral, medicines may be associated with the complexity of device usage. There is solid evidence that in COPD, adherence to inhalation medication is device-related [27]. Overuse is most pronounced for devices without a dose counter, devices with the ability to load a dosage without actual inhalation, or devices lacking feedback of correct
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ACCEPTED MANUSCRIPT inhalation. The design of the device seems to be related to underuse and overuse of inhaled medication. However, apparently there is no impact of inhaler device (multipledose versus single-dose inhalers) on COPD patients’ persistence, at least with LABAs. In fact, in a Dutch retrospective observational cohort study, persistence between users of multiple-dose and single-dose inhalers did not significantly differ [28].
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A Spanish cross-sectional multicentre study has shown that patients with COPD are more adhering to inhaled drugs than patients with asthma. Only being younger than 50 years of age and active working status were risk factors for non-adherence in the multivariate analysis, while having asthma remained in the limits of the significance [29]. In any case,
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non-adherence in patients with COPD is frequently unwitting, while that of asthma is most often erratic and deliberate.
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Older age coupled with memory loss and impaired cognitive levels lowers adherence to medications, in particular to inhalation therapy [30]. In particular, a recent prospective observational study of adherence to a regularly prescribed LABA/ICS combination inhaler by patients with COPD following discharge from hospital reported that the patient’s cognitive status may affect the patient’s ability to remember both when and how to use the inhaler [31]. Patients with poor executive functioning often display a “knowing–doing
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discrepancy.” Although they can report specific instructions, they cannot translate these into specific behavioural and motor plans and activity. Hence, abnormalities in the executive and memory domain may influence adherence through poor recall of inhaler
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technique and not remembering to use their inhaler [31]. Mastering the technique required to successfully utilize an inhaled medication delivery device is a challenging problem in the elderly, and improper technique is very common,
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even in patients who have received detailed instruction in their use [30]. In fact, physical and cognitive changes, the presence of arthritis or joint pain and also neuromuscular conditions like Parkinson’s disease or complications after stroke contribute to the difficulties that some elderly patients have with handheld inhalers [32]. In these patients, the ability to generate sufficient inspiratory flow across a dry powder inhaler (DPI) is compromised, irrespective of the presence of COPD [32], although there is evidence that lung function makes a contribution to technique errors even in those with good attempted adherence. For many patients, particularly those experiencing increased hyperinflation, it may not be possible to generate sufficient airflow for effective inhalation, and this leads to
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ACCEPTED MANUSCRIPT ineffective drug delivery [31]. The elderly may also find it difficult to actuate a pressurised metered-dose inhaler (pMDI) device [32]. All these things can adversely affect medication adherence in elderly patients. In order to overcome such disadvantages, and also to improve the adherence, aged people can use
could consider nebulizers [32].
6. How society can affect adherence in COPD
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the breath-actuated MDI that is easier to use than the pMDI or DPI. Alternatively, they
Frequently, health care systems create barriers to adherence by limiting access to health
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care, using a restricted formulary, switching to a different formulary, and having prohibitively high costs for drugs, co-payments, or both [33].
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Socioeconomic status is an intriguing factor in the search for determinants of populationlevel non-adherence to COPD because of its associations with economic, social, and education-related factors. Indeed, all these factors may affect regular medication use [8]. Socioeconomic factors that may affect adherence include poverty, illiteracy, low educational achievement, unemployment, insufficient social support, transportation issues, excessive medication and treatment costs, and environmental factors [34]. Unemployed,
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low-income patients, immigrants, and patients living alone are all at a higher risk of poor adherence to or, even, non-use of inhaled COPD maintenance medications [35]. Caregivers, especially spouses, may improve adherence in COPD. A study that aimed to
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evaluate the association between caregiver presence and adherence to medical recommendations among COPD patients showed that, compared with the “no caregiver”
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group, antihypertensive medications adherence was higher in the “spousal caregiver” and “non-spousal caregiver” groups, whereas LABA adherence was higher in the “spousal caregiver” group [36]. Patients in the “spousal caregiver” group had fewer current smokers compared with the “no caregiver” and “non-spousal caregiver”. Greater involvement of spousal caregivers likely translates into closer monitoring and a greater influence on patient behaviours, perhaps explaining why patients with spousal caregivers performed the best in all three categories. Minorities are consistently less adherent than general population [37]. This may be secondary to drug-related issues. Language barriers and cultural beliefs should be explored further to better understand their role in adherence.
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7. Methods to improve medication adherence in COPD Patient-health care professional, especially patient-physician or patient-pharmacist, communication is central to optimizing patient adherence. Building trust and developing skills for successful patient-provider communications require time, effort, knowledge, and practice [38]. However, the most often expressed barrier to improving patient-provider
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communication is inadequate time [38]. Taking extra time with those on multiple medications, where adherence is lower, is indispensable to guarantee patients understand the importance of not treating one condition at the detriment of another [37].
There is solid evidence that the impact of patients’ perceived burden of therapy on
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adherence might be modified by a better understanding of therapy, and consequently education may help reduce interruptions of COPD therapy [39]. Interestingly, education of
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patients, along with better co-ordination of care, showed significant improvements on COPD patients’ adherence [40] as well as fewer hospitalisations [41]. Also community pharmacists can have a positive and cost-effective impact in the management of COPD in relation to medication adherence and inhalation technique education, which in turn can decrease medication wastage, hospital admissions and
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severe COPD exacerbations [42]. However, the role of community pharmacists is still not fully studied or recognized, thus there is a clear need for more research. However, a 3 month randomized clinical trial (PHARMACOP trial) conducted in 170 community pharmacies throughout Belgium to assess the effectiveness of a protocol-based
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pharmaceutical care programme in patients with COPD showed that both primary outcomes, i.e. inhalation technique and medication adherence, were significantly improved
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more in the intervention group than in the control group [43]. A cost-effectiveness analysis of this trial documented that improving inhaler adherence in community pharmacies is a cost-saving strategy compared with usual care [44]. No standard intervention exists to improve adherence. However, it is likely that a multifactorial intervention focuses on motivation, knowledge and skilled inhalation technique (COPD information, dose reminders, audio-visual material, motivational aspects and training in inhalation techniques) is an effective approach to improving the therapeutic adherence in COPD patients [45]. In any case, adherence requires a behavioural change, an aspect that is related to individual interests and expectations, meaning that patients must be managed individually. Furthermore, the intervention is complex and time-
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ACCEPTED MANUSCRIPT consuming [45]. It has been highlighted that success of the ABC taxonomy within COPD needs a focus on unmet research through consistent use (and clear documentation of use) of the proposed terminology and recognized evaluation measures [46]. However, it must be interpreted and applied in the context of the specific characteristics of COPD, in which the inhaled route of
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therapy delivery is central, in particular, for its potential capacity to affect all steps of the adherence pathway negatively. In any case, producing strong research evidence requires careful selection of the best existing valuation approaches for the peculiar aspect of adherence and particular research question under consideration and clear reporting of the
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research question(s), valuation method(s), results and specific implications, and relevant context.
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Although more research is needed into the most effective approaches for optimizing medication adherence in patients, mainly seniors, with COPD, there are a number of practical opportunities for health care practitioners to intervene to support medication adherence [47]. In effect, there is a need to investigate the specific attitudes toward medication use and the adherence behaviours of seniors with COPD, develop interventions that tackle the adherence barriers specific to older patients (e.g., cognition,
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polypharmacy, and immobility), identify methods for ongoing inhaler technique support outside the professional health care environment, evaluate the role of multiple inhaler types prescribing on medication adherence and that of electronic monitors and reminders for missed doses in elderly patients with COPD. Furthermore, it is important to evaluate
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the role of secondary care experiences on medication adherence (i.e., direct-to-ward versus. to ward via the emergency room). These are all things that can be done
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immediately and do not require more than the will and time to make them. Likely, the most realistic approach is to keep in mind that non-adherence is always possible and probable. Thus, one has to remember C. Everett Koop, a former Surgeon General of the USA, who put into words something that is evident, but very frequently forgotten “Drugs do not work in patients who do not take them”. However, since adherence can be broken down not only at the initiation or persistence stage, but also, and mainly at the implementation stage, it is always imperative to consider that no drugs exert maximal effects unless patients take them as prescribed.
Conflict of interest
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ACCEPTED MANUSCRIPT All authors declare no conflicts of interest regarding the publication of this manuscript.
Funding This article did not receive any specific grant from funding agencies in the public,
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commercial, or not-for-profit sectors.
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ACCEPTED MANUSCRIPT Table 1 - Methods to measure adherence in COPD Advantages It is the most scientifically sound
Adherence measured as the percentage of doses taken/doses prescribed
It is easy to use and inexpensive
Electronic monitors
They provide accurate and reliable records of dosage
Disadvantages It is expensive and invasive and also reflects many factors that can result in pharmacokinetic variations. Furthermore, blood or urine drug levels cannot quantify the manner in which the patient has taken the medication or detect fluctuations in compliance between clinic visits. It only assesses whether the correct number of pills have been removed and does not provide information on dose timing. Furthermore, the patients can switch medicines between bottles/boxes and may even discard pills before visits in order to appear to be following the regimen They are expensive, subject to malfunction and cannot confirm ingestion. Furthermore, the patients may open the container and not take the medication, take the wrong amount of medication or take multiple doses out of the container at the same time (or place multiple doses in another container). It is not reliable because intentional activation of the device multiple times consecutively over a short period of time even immediately prior to the visit can wrongly suggest optimal adherence It cannot assess ingestion or pattern of use and ‘dose dumping’ remains undetectable. Furthermore,
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Method Biochemical evaluation of drug level to confirm the intake
Canister weighing
It is relatively simple and easy to implement
Analysis of pharmacy records
It provides evidence of drug refill patterns
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refill records are limited in that they may be missing information, are restricted in the types of adherence that can be assessed (e.g., interdose intervals cannot be calculated), and may be too troublesome for providers to incorporate into practice.
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ACCEPTED MANUSCRIPT Tabella 2 - Self-reported adherence methods Patient interviews, with specific questions regarding the accuracy •
Haynes and Sackett method (HST) (self-reported assessment of adherence). – Patients asked whether they ever miss their pills and, if so, to state their
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current prescriptions and the average number of tablets missed per month. Standardized, validated, adherence specific questionnaires. •
Morinsky Green test (MGT) (attitude towards treatment).
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– Good adherence to be when the patient is able to answer these four questions suitably
Do you ever forget to take your inhaled medication?
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Are you careless at times about taking your inhaled medication?
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When you feel better, do you sometimes stop taking your inhaled medication?
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Sometimes, if you feel worse when you take the inhaled medication, do you stop taking it?
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Batalla test (BT) (the patients’ understanding of their illness). – Good adherence to be when the patient is able to answer these three questions suitably
Is COPD a lifelong disease?
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Can you control this disease by quitting smoking and/or with
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medication?
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Mention one or more organs that can get damaged by COPD.
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ACCEPTED MANUSCRIPT Figure 1 - Patients, physicians and society influence patient maintenance medication
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adherence in COPD
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Highlights The level of medication adherence in COPD patients is very low.
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Approaches to assess adherence of COPD are burdened with important limitations.
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Patient views on therapy effectiveness are powerful predictors of reported adherence.
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The physician can affect adherence in COPD with his/her prescription.
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In COPD, adherence to inhalation medication is device-related.
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•