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Adherence: a review of education, research, practice and policy in Spain

Aims: To describe medication adherence education, practice, research and policy efforts carried out by pharmacists in Spain in the last decade. Methods: A literature review using Medline and Embase was conducted covering the last ten years. Additional pharmaceutical bibliographic sources in Spain were consulted to retrieve articles of interest from the last decade. Articles were included if a pharmacist was involved and if medication adherence was measured or there was any direct or indirect pharmacist intervention in monitoring and/or improving adherence. Articles focusing on the development of tools for adherence assessment were collected. Pre- and post-graduate pharmacy training programs were also reviewed through the Spanish Ministry of Education and Science website. Information regarding policy issues was gathered from the Spanish and Autonomous Communities of Education and Health Ministries websites. Results: Pharmacists receive no specific training focused on adherence. There is no specific government policies for pharmacists in Spain related to medication adherence regardless of their practice setting. A total of 24 research studies met our inclusion criteria. Of these, 10 involved pharmacist intervention in monitoring and/or improving adherence and 14 assessed only adherence. Ten studies involved hospital pharmacists working in collaboration with another healthcare professional. Conclusions: At present in Spain, the investigative role of the pharmacist is not well developed in the area of medication adherence. Adherence improvement services provided to patients by pharmacists are not implemented in a systematic way. However, recent efforts to implement new initiatives in this area may provide the basis for offering new cognitive services aimed at improving patient adherence in the near future.


INTRODUCTION
Non-adherence to drug therapy is a frequent and well known phenomenon in our environment and constitutes a major problem, particularly with chronic diseases, where it has a direct impact on patient health and is a principal cause of treatment failure. In fact, the World Health Organization (WHO) considers non-adherence to be a high priority public health issue. 1 In addition to its health impact, the economic impact of non-adherence must be considered. 2,3 Ineffective treatment resulting from undiagnosed non-adherence to therapy is quite frequent. 4 Resultant unresolved symptoms may lead to additional diagnostic testing as well as dosage increases and/or unnecessary additional medications. Large amounts of time and money are invested in the search for new and more effective medications, while little attention is paid to whether or not patients are taking their medications, or taking them correctly.
The magnitude of non-adherence to drug therapy in Spain varies across studies depending on the type of treatment given and the measurement method applied. For example, a number of studies related to adherence by hypertensive patients to the recommendations given by their healthcare professionals have shown that non-adherence in hypertension varies between 40% and 71%. [5][6][7] Thus it is critical to identify and monitor non-adherence as part of daily clinical practice.
There are direct and indirect methods for measuring adherence. 8 Direct methods consist of measuring the medication, its metabolites, or other biochemical markers in bodily fluids. Though objective and specific, such methods are seldom used in routine practice due to their technical difficulty and high cost. Indirect methods are based on information provided by the patient via instruments such as clinical interviews, self-administered adherence questionnaires, pill counts, medication electronic monitoring systems (e.g. MEMS™ electronic monitors), and adherence to medication refills. These methods are useful in daily practice, although they may overestimate adherence. Patients are known to improve their adherence when they are being observed. 8 Thus results must be interpreted with some caution. However, electronic monitoring and pill count have shown the best validity and are usually used as gold standards to calculate the validity of other indicators. 8 Currently, several terms are used to describe when patients take their medication according to the instructions of healthcare professionals. Terms such as compliance or adherence to treatment are used in both healthcare practice and research. Differences notwithstanding, it is critical that this concept reflects patients' active participation in selecting and maintaining a therapeutic regimen 9 , as well as their understanding of the information given about their specific diseases and treatment. 10 WHO states that adherence must be understood as a behavior in which the patient acts rationally on all recommendations provided by the team of professionals in the treatment of a disease. 1 Understanding the reasons that drive a patient to nonadherence may help in meeting the stated therapeutic objectives. 11 Non-adherence to treatment depends not only on the patient and the treatment characteristics, but also on factors related to the healthcare professionals treating the patient. Thus the problem must be addressed in a multidisciplinary basis.
In this context, community pharmacist is considered a professional both with the knowledge and the best availability to collaborate in ensuring correct use of medications and optimal patient adherence to treatment. A study on the effect of pharmacist intervention via written patient information on patients' adherence to antibiotic treatment showed an increase in adherence, and thus improved treatment results. 12 These pharmacist patient support activities are part of the concept of pharmaceutical care, which is understood as the participation of the pharmacist in the assessment of clinical outcomes related to the use of drug therapy 13,14 , and more generally, the pharmacist's role in promoting and preserving health. In dispensing and over-the-counter (OTC) prescribing, the pharmacist must instruct the patient on the use of medications. Another patient-related task, which aims among others things at rationalizing and improving the use of medications, is medication review with follow-up. [15][16][17] This activity includes the implementation of appropriate processes for preventing, monitoring and improving adherence to treatment in order to achieve healthcare outcomes. This paper is a review that covers key aspects of the role of the pharmacist in Spain as it relates to adherence, specifically: Spanish national health policies in this area, the relevant training given to pharmacists in Spain, the research studies carried out and the services implemented to measure, monitor and improve adherence.

Education in medication adherence
Presently, there are 18 Pharmacy Schools in Spain. Of these, nine offer the title of Graduate Pharmacist in compliance with the Bologna Declaration (whose aim is to regulate university degree programs across all of Europe). 18 The remaining nine schools offer the title of Bachelor of Pharmacy, which is being phased out. All Pharmacy School programs in Spain were reviewed to identify any pre-or postgraduate courses related to medication adherence in their curricula. This was done by reviewing the Spanish Ministry of Education website. 19 Both Graduate Pharmacist and Bachelor of Pharmacy degrees, as well as postgraduate educational courses, offered by Spanish Universities were reviewed. From this information, a search was performed to reveal which Universities offer pharmaceutical care courses that include any adherence related topic.

Research, practice and policy in medication adherence
A literature review was conducted to identify published literature on research projects or programs implemented in Spain that have focused on medication adherence in a pharmacy setting. The databases consulted were MEDLINE and EMBASE; both searches were limited to Spain in the last ten years.
The Medline search was performed on the basis of the following MeSH terms ("Patient Compliance", "Medication Adherence", "Pharmacists", "Pharmaceutical Services", "Pharmacy Administration", "Legislation, Pharmacy", "Societies, Pharmaceutical", "Insurance, Pharmaceutical Services"). In Embase, a number of search terms were used: "Patient Compliance", "Pharmacists", "Pharmacy", 'Health care organization", "Management", "Spain". The following professional journals were also manually searched to identify additional research projects and adherence programs implemented by pharmacists within Spain: Pharmaceutical Care, Offarm, Farmacia Profesional and Ars Pharmaceutica.
Articles retrieved in these searches were reviewed by three independent researchers to verify that they met the inclusion criteria. Namely, articles were included in the review if a pharmacist was involved and if medication adherence was measured or there was direct or indirect pharmacist intervention in monitoring and/or improving adherence. Articles focusing on the development of tools for adherence assessment were also selected.
To assess policy projects on medication adherence in Spain, Ministry of Education and Ministry of Health and Social Policy websites, as well as corresponding websites from every 17 Autonomous Community, were searched.

Pharmacist education in adherence
Pre-graduate education None of the programs offered by the 18 universities had courses which focused specifically on adherence. However, a "pharmaceutical care" course was offered in seven universities. In particular, three of the schools that award the Graduate Pharmacist title had made this course mandatory while four others offer it as an elective course. These courses cover the three main services that, according to the Spanish Forum of Pharmaceutical Care 15 , constitute the philosophy of practice.
The Pharmacy White Paper [Libro Blanco] 20 , published by the Spanish National Institute of Accreditation and Quality Evaluation (ANECA) [Agencia Nacional de Evaluación de la Calidad y Acreditación] calls for making pharmaceutical care a mandatory subject, and is the basis for a recent national regulation (CIN/2137/2008) delineating the competencies that pharmacy students must acquire. Key among these competencies are the following: the proficiency to identify and assess medication related problems, preparedness for participation in pharmacovigilance activities, and the ability to carry out the clinical and social roles of a pharmacist in accordance with the pharmaceutical care cycle.
Post-graduate education A growing number of pharmaceutical care specialization courses are being offered by Spanish universities. While not exclusively focused on medication adherence, these courses teach the required skills to prepare pharmacists to implement adherence improvement strategies in any professional setting. Notably, students learn about how to deal with patients, with a focus on improving communication skills.
Medication adherence was the primary parameter assessed in five of the studies 12,25-28 , and a secondary parameter in the remaining five studies. 21,[22][23][24]29 In terms of disease type, six studies focused on chronic diseases: acquired immunodeficiency syndrome (AIDS) 23 , type II diabetes 26,29 , hypertension 24,29 , dyslipidemia 29 , hepatitis C 21 , and cardiac insufficiency. 22 Two studies dealt with antibiotic adherence 12,28 , and in two studies, no disease type was specified. 25,27 Adherence monitoring was carried out by several methods or combinations of methods: clinical interview 24,25 , modified Morisky-Green questionnaire 23,26 , Simplified Medication Adherence Scale, SMAE (Escala Simplificada de Adherencia a la Medicación) together with the Simplified Medication Adherence Questionnaire (SMAQ) and self-reported patient adherence 23 , a non-validated questionnaire 27 , pill count 21,22,29 , prescription record analysis 23,27 , adherence to scheduled pharmacy visits 28 , and Direct Observed Treatment (DOT). 28 Four studies involved specifically designed educational interventions. 12,21,22,28 Six studies involved Medication Review with Follow-up (five via the Dader Method [24][25][26][27]29 and one with a different method 23 ). All of them utilized one of the abovementioned measurement methods or combination of methods. Seven of these articles showed significant adherence improvement after pharmacist intervention 12,[22][23][24][25][26][27] , although only three correlated pharmacist intervention with clinical parameters to demonstrate the effectiveness of the intervention 23,24,26 (reduction of glycosylated hemoglobin, blood pressure and viral load). The key characteristics of these studies are summarized in Table 1.

Pharmacy practice on adherence
In the Spanish pharmacy environment, there is no established service offered specifically for adherence. However, reports studied for this review indicated that pharmacists do offer services that enable measurement, monitoring, and improvement of patient adherence to medication therapy. These services include pill-organizers 44 , Medication Review with Follow-up services [23][24][25][26][27]29 , and hospital protocol programs aimed at detecting adherence problems. 45 National policies related to medication nonadherence Spain is a European Union member with a population of 46 million. It has a semi-federal structure with 17 "Autonomous Community" states, which are further divided into 52 provinces. 46 There are no specific government policies related to medication adherence currently in place in Spain. However, it is important to note that there are health policies at the professional level that address the role of the pharmacist in patient adherence to treatment. The recent health policy and consensus document on hypertension in Spain 47 is a good example of such a professional level policy. In this document, the various scientific societies and signatory organizations specify the need to develop pharmacy educational programs that raise patients' awareness of the impact of adherence on their health.
The recent consensus document published by a panel of experts from the Spanish Pharmaceutical Care Forum [Foro de Atención Farmacéutica] 15 defines common terms and services and describes procedures for the practice of pharmaceutical care, including a proposal to Spanish software companies recommending implementation of certain agreed upon procedures in software programs for Spanish pharmacies. In this sense, a national strategy is emerging, at least in the area of pharmacy software, for the most important pharmaceutical care services, namely dispensing and OTC prescription, and medication review with follow-up. 15 Although the outcomes of this development are not yet known, it is seen as a good opportunity for the further development of the pharmacist's role in patient adherence. Nevertheless, at the governmental level, initiatives being carried out in some of the Autonomous Communities in Spain have shown improvement in addressing the issue of adherence by community pharmacies. 49 For example, the broad adoption of electronic prescriptions enables pharmacists to know their patients' prescription and dispensing histories. This strategy could serve to strengthen the role of the pharmacist in improving adherence.
Among the strategies for improving adherence, three initiatives implemented so far in several Autonomous Communities deserve mention. 28,50,51 In one case, a pilot collaborative effort is being carried out between local pharmacist professional associations and municipal home care services with the aim of improving medicine use of home-bound patients. The program consists of a dose administration aid, which is given to the patient at twice-monthly pharmacy visits and returned by the patient or caregiver at the next visit with any "pills not taken". 50 Another national project, proposed in 2009 by Spanish health authorities, involves improvements in care for chronic and multiple-drug patients. Specific project activities include the contracting of qualified healthcare professionals for medication management, specifically pharmacists who can systematically review treatment effectiveness, promote rational drug use, and help patients adhere to their drug treatment. 51 Finally, reimbursement of community pharmacist cognitive services has been established as part of a multidisciplinary care program focused on tuberculosis patients at risk for non-adherence. Pharmacists receive a standard fee per patient per month for directly supervising the delivery of tuberculosis medication, and for educating patients on adherence. 28

DISCUSSION
Pre-graduate pharmacy education in Spain seems to be insufficient to achieve the skills required to manage adherence issues in the pharmacist's daily practice. With regard to the Spanish policies on adherence in the pharmacy setting, it appears there are also not sufficient efforts being implemented at the professional level to adequately enable implementation of new cognitive services and growth in the pharmacist's role. Such professional level efforts should be reinforced by government level strategies, as has been done in other countries [52][53][54] , through the establishment of reimbursement to pharmacists and promotion of collaborative programs within the health care team.
It should be noted that the studies selected for this review revealed certain problem areas in research methodology related to adherence. One key problem is the reliability of adherence measurement methods. Many studies measured adherence with methods that were unreliable or not often recommended, such as the use of the Morisky-Green test regardless of its validity for the specific disease, or the use of clinical interviews. Indeed, the researchers themselves when using a combination of methods revealed that there is little agreement between them. [34][35][36]41 None of the studies reviewed used electronic monitors, the method recommended as the reference standard to measure the validity indicators for the other indirect methods. On the whole, few studies have monitored adherence via electronic monitors in Spain, likely because of the high cost of MEMS devices. MEMS have likewise not been used much in Australia according to a similar review conducted there. 53 In terms of pharmacist involvement, more than half of included studies were carried out by hospital pharmacists. This highlights the low level of involvement of community pharmacists in adherence related activities, when in fact these pharmacists are in a unique position to promote medication adherence, being the last point of contact with the patient before beginning use of the medications. Strategies should be formulated to achieve greater involvement of the community pharmacist in promoting adherence.
Only four of the studies [24][25][26]33 looked at the impact of improved adherence on health results, even while ethical standards for adherence research specify that any study which evaluates and improves adherence should not only contribute these isolated data points, but should also describe the clinical outcome benefits obtained. 55 The only studies found to correlate adherence with health outcomes did not use the most valid designs and therefore could lead to erroneous conclusions. 24,25,33 The above limitations should be taken into account in the design of future research studies. However, despite the possibility that these limitations may have introduced biases in prior studies, it is noteworthy that the results of most of the studies suggested that pharmacist intervention can improve patient adherence and/or patient's health status. 12,21,22,24,[26][27][28] In the experimental studies with control groups that were identified in our search, adherence in the experimental group patients was higher than in controls. 12,22,26 These findings reinforce the statement that a pharmacist can play an important role in improving adherence when delivering information about medication, thereby helping patients to understand and remember prescribed dosages and educating them about the importance of following the recommendations of health care professionals. 22,26 CONCLUSIONS Presently, the investigative role of the pharmacist in Spain is not yet well developed in the area of medication adherence. Adherence improvement services provided by pharmacists to patients are not widely implemented in a systematic basis. However, recent efforts to implement new initiatives in this area may provide the basis for offering new cognitive services aimed at improving patient adherence in the near future. Pharmacists, regardless their practice setting, should be aware of the existence of a societal need for the rational use of medicines and, more specifically, for improving adherence to prescribed medical treatments.
The most frequent DRPs were due to medication adherence problems (30% of patients).
Significant differences were found in viral loads between the 1st and 5th visit. No direct relationship between DRPs and adherence was found, although increasing the number of visits between the first and the fifth visit did significantly affect viral load.

Study Outcomes Assessed
Quantitative Results for Medication Adherence and Health Results a A patient was considered adherent if 80-110% of the prescribed medication was used. b Drug-related problem (DRP): Circumstances that have caused or might cause a negative result associated with the medication. c Negative outcomes associated with medication (NOM): Undesirable changes in patient's state of health attributed to the use (or non-use) of a medication. d NOM refers to a patient health problem or undesirable health state attributed to use or non-use of medications. In the article this appears as drug-related problem (DRP) which is the older nomenclature. the new nomenclature, a DRP became a NOM. Nowadays a DRP is defined as a situation in which in the process of use of medicines cause or may cause the appearance of a negative outcome associat with medication 56 e Does not specify criteria for non-medication adherence. f Patients were defined as adherent if 95% to 100%, partially adherent if 85%-95%, and nonadherent if less than 85% of the prescribed medication was used. g To estimate the percentage of adherence the following formula was used: Number of pills used/Number of pills that should have been used x 100.Patients are considered adherent when their scores located between 80-100%. Patients are described as hyper-adherent if they get a score higher than 110% and nonadherent with less than 80%. h Simplified Medication Adherence Scale (SMAE) i Simplified medication adherence questionnaire (SMAQ)  Clinical interview with a nurse: Doses missed during the 4 days before the visit. Patients were considered nonadherent if they had taken <90% of prescribed doses of at least one drug.  Adherence to medication refill: Delay in collection of drugs at the pharmacy. Patients were considered nonadherent when they reached a cumulative delay of more than 9 days.  Indinavir levels: Non-adherence was determined when plasma levels were undetectable.

N/106 (%) 95%CI
Total  Patient self-reporting: Patients were considered nonadherent if they took <80% of their prescribed zidovudine in the month before the visit.  Medication refill at the pharmacy: Patients were considered nonadherent if they failed to keep pharmacy appointments.  Changes in mean corpuscular volume: Patients were considered as adherent if the mean volume was >97 mm 3 or the increase was >18 mm 3 above the baseline mean volume.
Occurrence of opportunistic events: occurrence of opportunistic events:  Double-therapy group: 6 (31.6%) non-adherent patients and 0 adherent patients had at least one opportunistic event. The difference between both groups was statistically significant.  Triple-therapy group: 4 (16%) non-adherent patients and 0 adherent patients had at least one opportunistic event. The difference between both groups was not statistically significant.  Clinical interview: Doses missed in the 4 days prior to the interview. Patients were considered nonadherent if they took < 90% of the total prescribed dose of at least one drug.  Medication refill: Delay in collection of prescribed drugs from the hospital pharmacy over the previous 3 months. Patients were considered nonadherent when they reached a cumulative delay of more than 9 days.  Variables: clinical information, sociodemographic information, risk factors for HIV infection, adverse effects, self beliefs and TARGA selfperceived effectiveness, alcohol and recreational drugs consumption, symptoms of depression in the last week, and capability for selfcontrol in the last month.