Review question/objective

The objective of this systematic review is to identify the best available research evidence related to the effectiveness of educational and supportive interventions for improving adherence to inhalation therapy in people with chronic respiratory diseases, focusing on measures of adherence and health outcomes.

The specific review questions to be addressed are:

1. What is the effectiveness of educational and supportive interventions for improving adherence to inhalation therapy in terms of inhalation regimens and inhalation techniques in people with chronic respiratory diseases?

2. What is the effectiveness of educational and supportive interventions for improving adherence to inhalation therapy on health service utilization and patient outcomes including symptoms, pulmonary function, and quality of life?

3. What is the effectiveness of various designs, in terms of components, modes and intensities, of educational and supportive interventions for improving adherence to inhalation therapy?

Background

Chronic respiratory diseases refer to "chronic diseases of the airways and other structures of the lung" (p. 5).1 Common preventable chronic respiratory diseases include asthma, chronic obstructive pulmonary disease (COPD), and respiratory allergies. In 2007, the World Health Organization (WHO)1 estimated that 300 million people had asthma and 210 million had COPD and many more suffered from other chronic respiratory diseases; that in total accounted for 4% of global burden of disease. Every year, four million people die due to chronic respiratory diseases.1 In Hong Kong, recent studies show that the prevalence of asthma in children aged 6-7 years was 9.4% while the prevalence of chronic respiratory diseases (including asthma, chronic bronchitis and emphysema) in elderly populations (aged over 70) was 16.6% in 2003.2,3 Chronic lung disease was ranked the third leading cause of morbidity and mortality in chronic diseases in 2009.4 As the number is still increasing, chronic respiratory diseases will be a great global health problem in the next two decades.1 It is therefore important to prevent and manage the diseases properly in order to reduce the incidence and severity of the diseases as well as reduce the burden on the health care service.

INHALATION THERAPY

Inhalation therapy is a very common and important mode for respiratory care in the 20th century.5 It is defined as "a treatment in which a substance is introduced into the respiratory tract with inspired air" (p. 972).6 Inhalation therapy may include administration of oxygen, water and/or drugs. This review will mainly focus on inhalation of a drug, known as aerosol therapy. By and large, over 60% of what respiratory physicians do in clinical practice is related to aerosol therapy.7 The inhalation route of administration has an advantage over the oral or parental route to treat pulmonary diseases, as the aerosol drugs are directly delivered and deposited in the lung. Advantages of such administration include relatively lower doses required, faster onset of effect with minimal systemic exposure and less systemic adverse effects.5 Although inhalation therapy has its advantages, patients have to adhere to the recommended inhalation regimen in the hope to achieve treatment success.

ADHERENCE

Adherence is defined by WHO as "the extent to which a person's behavior - taking medication, following a diet, and/or executing lifestyle changes, corresponds with agreed recommendations from a health care provider" (p. 3).8 Several studies assessed the adherence rate of therapy in general and inhalation therapy in particular. Dimatteo conducted a systematic review to examine studies concerning patients adherence to the medical treatment in the past 50 years.9 It was found that the average adherence rate to medical treatment was 75.2%, while adherence in respiratory disease was only 68.8%, which was lower than for other chronic diseases. For inhalation therapy, the adherence rate was even lower, which was around 50%.10

There are several factors affecting patients' adherence to their medications and such factors can be classified as unintentional non-adherence or intentional non-adherence.11 For unintentional non-adherence, patients from this group are willing to adhere to the treatment but encounter difficulties. In several related studies, patients reported that the regimen of inhaled corticosteroids were hard to follow and inhalers were difficult to handle.12,13 Increasing complexity of the medical regimen was considered as one of the contributing factors for unintentional non-adherence and caused confusion amongst patients, especially the elderly with multiple comorbidities.13-16 Simply forgetting to use an inhaler was ranked second amongst major causes for inhaler variance and this was not only confined to the elderly.17 Memory problems, due to cognitive decline as age increases, physical difficulties in handling the medication and poor vision also led to suboptimal inhalation adherence. 11,13,14,18,19

Intentional non-adherence occurs when people prefer not to follow the advice from health care professionals after rational thinking around the pros and cons of a treatment. Mostly this decision was based on beliefs and experiences about the disease and treatment, which were stronger predictors of adherence to medications than socio-demographic factors or clinical factors.14 Studies demonstrated that when comparing groups of patients with higher medication adherence with groups with poor or decreased adherence, the latter group often had insufficient or minimal understanding about their illness and its management and felt that inhalation medication could not help them breathe easier.12,14,17Bourbeau and Bartlett stated that patients had lower adherence to inhaler steroid than rescue medication because they felt no immediate symptom relief.13 Furthermore, worrying about becoming addicted and experiencing side effects of the medication was common.12,14,15 This range of beliefs and experiences would induce patients to adjust their recommended regimen according to their symptoms and result in poor adherence.

INHALATION TECHNIQUE

Besides adherence to the inhalation regimen, the inhalation technique is also indispensable to the effectiveness of inhalation therapy.20,21 A proper inhalation technique requires correct steps and a suitable inspiratory flow pattern to deliver the optimal dosage of drugs to the lung. 5,7 An ineffective inhalation technique results in under delivery of the medication. This can be regarded as a form of a non-adherence indicator or measure.13,15 A systematic review has shown that a large proportion of asthma and COPD patients who use dry powder inhalers (DPIs), have an inadequate inhalation technique, though the results varied depending on the types of devices and the assessment methods used. In the worst case, up to 94% of adults used their inhaler incorrectly.22 The improper use of pressurized metered-dose-inhalers (MDIs) was as high as 71% in asthma patients.23 Such a high handling error rate may be due to insufficient instruction regarding the proper inhalation technique. A study reported that among 224 patients who were currently using DPIs, only 63.6%-73.4% of patients had received prior training in inhalation techniques.18 Misperception of the correct inhalation technique was identified as another crucial factor to poor inhalation technique. Studies revealed that all participants thought their inhalation technique was correct after having received inhalation instructions. However, only 78.5% of them demonstrated all critical steps correctly.24 When patients used more than one type of inhalation device, studies found the risk of making a significant error increased two-fold (odds ratio 2.2, 95% CI: 1.1 - 5.0).25 Unfortunately, health care professionals also often lack adequate skills with inhalers. Self et al.26 reviewed 20 relevant studies and found that only up to 28% of doctors, 22% of nurses and 65% of respiratory therapists could perform an "all-steps" inhalation technique correctly. All aforesaid factors contribute to the prevalence of poor inhalation technique in patients with chronic respiratory disease.

IMPACT OF POOR ADHERENCE TO INHALATION THERAPY

Not surprisingly, poor adherence to a medication regimen and inhalation technique are closely related to poor health outcomes, increasing utilization of health services and economic loss due to ineffective treatment. A study performed by Takemura et al.21 to assess the relationship between adherence to inhalation therapy and clinical outcomes showed that patients with high adherence had lower frequency of asthma exacerbation (r= -0.19, p= 0.021) and emergency room visits (r= -0.19, p= 0.042), and better health-related quality of life (HRQOL) (r= -0.22, p= 0.024). In contrast, studies demonstrated that both low adherence to drug therapy and poor inhaler technique resulted in poorer symptom and disease control.23,27 George et al.11 and Vestbo et al.28 also identified poor adherence to medication as a key factor associated with emergency hospitalization among COPD patients. Furthermore, Fink and Rubin estimated there were US$5-7 billion lost every year directly due to poor inhalation techniques (based on the assumption that 28%-68% of patients use inhalers incorrectly).7 This highlights that adherence to inhalation therapy can have a great impact on both personal health and health services. There is a need to provide effective interventions that improve the adherence to inhalation medication and inhalation technique.

INTERVENTIONS TO IMPROVE ADHERENCE OF INHALATION THERAPY

The adherence problems described are widely recognized in the research. Based on the root cause, a number of interventions for overcoming non-adherence have been introduced. To target non-adherence driven by memory loss and forgetfulness, adherence aids and reminder systems such as provision of written instruction or timers have been suggested.11,13 Another way is to help patients to develop their medication plans to fit the complex medication regimen into their daily lifestyle routine.7,14 To the non-adherence driven by patient beliefs and experiences, education, periodic monitoring and reinforcement are in widespread use in clinical areas to deal with the problems.11,22,27

Educational interventions might be as simple as provision of written material alone, instruction or demonstration in inhalation techniques, or as complex as a training program or structured program including provision of comprehensive information on disease pathology, treatment plan, medication and self management with action plan. Studies have demonstrated that both simple educational interventions and comprehensive self-management education and training programs have positive effects on the adherence to inhalation regimen and inhalation techniques to various extents.19,29-32 According to a study by Kamps, Brand and Roorda, training with patient return-demonstration rather than instructor's demonstration can enhance correct inhaler use (OR 2.6, 95% CI= 1.1-6.4; p= 0.04).24 It was emphasized that repeating inhalation instructions enhanced patients not only in achieving but also retaining a correct inhalation technique. Another study examined 727 patients with asthma enrolled in a single inhaler technique training session with the median duration lasting for six minutes (range, 1-30 minutes).29 The study showed that even simple inhaler training could help improve inhaler technique as well as adherence and consequently asthma control of the patients. Press et al.19 also found that patients with impaired vision or inadequate health literacy were able to master inhaler technique after instruction.

Often, inhalation techniques and medication adherence are incorporated into self-management educational programs. A study by Janson et al.30 stated that individual self-management education improved adherence with inhaled corticosteroid in patients with asthma. Patients in the intervention group, after seven weeks, had increased inhaler adherence from 70% to 91% whereas those in the control group had decreased adherence from 65% to 62% (p= 0.01). Symptom severity and pulmonary function were also improved in the intervention group compared to the control group however, no statistically significant difference showed in between-group comparisons.

In addition to education, some enhanced support interventions are highly recommended, such as self-monitoring of symptoms, by regular measurement and recording of either peak expiratory flow or symptoms, or the medication plan as mentioned previously. These are tailored interventions to overcome the barriers so as to change patient behaviors effectively.13 The periodical review of patient inhaler adherence levels and giving reinforcement during each visit to enhance adherence is suggested in the 2011 version of Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline. 33

Psychosocial interventions such as concordance interview, counseling and problem-solving are some of the most effective interventions to reduce the barriers to adherence and to increase patient-health care professional interaction.13,14 Stiegler et al. suggested that counseling allowing patients to discuss their willingness to adhere should be included in the program in addition to education.34 Their findings showed adherence rates with asthma medication increased from 22% to 63% after six months. All of the above approaches aim at overcoming the problems associated with non-adherence and hence to improve adherence to inhalation therapy.

A systematic review conducted to evaluate studies published between 1992-2003 assessed interventions to improve adherence to inhaled corticosteroid among asthma patients.35 It revealed that among sixteen included studies that investigated educational interventions, only nine of them showed improvement in patient adherence compared with controls, while the other studies showed no difference between the intervention groups and control groups. However, this review only summarized the study's results. There was no synthesis of the effects of the interventions on adherence to inhalation therapy.

A systematic review of interventions for enhancing medication adherence with prescribed medication for medical problems (except addictions) showed that written information, phone follow-ups and counseling were useful for adherence in short-term treatment. In addition a combination of interventions such as information, counseling, reminders, reinforcement, psychological therapy and so on were more effective for long-term treatment.36 However, this systematic review included studies of various types of disease groups and interventions and the authors were only able to perform qualitative analysis owing to the heterogeneity of the subjects and interventions. In a subgroup analysis, a narrative approach was used to analyze the adherence intervention on asthma and COPD.36

It is clear from the literature that patient adherence to inhalation regimen and inhalation techniques are crucial to an effective inhalation therapeutic treatment. However the adherence rate is generally lower and consequently the therapeutic effect is sharply reduced in patients with chronic respiratory disease. Worsening symptoms and poorer health outcomes are unavoidable due to poor control of the disease. Intervention strategies to improve adherence are warranted, and it appears that past research has focused on educational interventions. There are several systematic reviews regarding the effectiveness of educational interventions37, self-management education38,39 and limited patient education programs 40 on health outcomes and the use of health care services among patients with a diagnosis of COPD and asthma. However, there is a lack of reviews examining the effects on improving adherence to inhalation therapy. Moreover, interventions other than educational strategies to improve adherence have not been given enough attention. A preliminary search has already been performed in the Joanna Briggs Institute (JBI) Library of Systematic Reviews, The Cochrane Library, MEDLINE, CINAHL, DARE and PROSPERO databases. There was no systematic review identified which investigated improving adherence. Thus a systematic review is warranted to examine the effects of various interventions to promote adherence to the inhalation therapy in order to optimize the therapeutic effect and identify the most effective intervention.

Inclusion criteria

Types of participants

This review will consider studies that include adults aged 18 or above, with a clinical diagnosis of chronic respiratory disease and prescribed self-administered inhalation therapy as a long term regular treatment, irrespective of the type of inhaler used. For the purposes of this review, "chronic respiratory diseases" is defined by WHO in 2007 as "the chronic diseases of the airways and other structures of the lung" (p.5).1 Inhalation therapy is defined as "a treatment in which a substance is administered to the respiratory tract with inspired air".6 This review will focus on inhalation of drugs. Those studies with prescribed administration of oxygen and water will be excluded. There is no universal standard for how long a treatment is undertaken to be defined as a "long term treatment". Acute episodic drug treatments, such as a course of antibiotics, will be excluded.

Types of interventions of interest

All educational interventions, with or without supportive programs, designed to improve the chronic respiratory disease sufferers inhalation technique and adherence to their prescribed inhalation therapy will be considered. Those studies that involve comparison of different types of inhalation medications, inhaler devices or inhalation methods to improve the adherence to inhalation therapy will be excluded. For the purpose of this review, educational and supportive interventions are defined as follows:

* Educational interventions that involve transfer of information regarding inhalation medication and inhalation techniques in any forms: written, verbal, visual or audio. The educational program can be as simple as provision of written material alone, verbal instruction, and/or demonstration of inhalation techniques or can be as comprehensive as a self-management education program and skill development training.

* Supportive interventions include enhanced support such as self-monitoring (i.e. regular measurement and recording of either peak expiratory flow or symptoms); regular review of adherence by health care professionals (i.e. telephone follow-up or scheduled clinic follow up) or psychosocial therapies including concordance interview, counseling, problem solving and reinforcement.

Types of outcomes

The primary outcomes of interests include:

* Medication adherence is defined as the extent of inhalation medication used by a patient corresponding to prescription by a physician, measured by subjective methods such as self-reported adherence (e.g. Morisky score41); or by objective methods such as prescription refill rates, electronic monitoring or measurement of inhaler weights. The adherence rate (%) is calculated based on the result obtained from objective measurement (actual consumption of medication) and the total amount of medication prescribed.

* Inhalation techniques consists of "steps" and "inspiratory flow", which is assessed by observers using specific checklists to check the step according to inhaler device type or using test device to check the peak inspiratory flow.5,7

The secondary outcomes of interests include:

* Symptoms including levels of dyspnoea and level of disease control, measured by, for example frequency of night time awakening, the shortened version of Asthma Control Questionnaire (ACQ)42, Modified British Medical Research Council questionnaire (mMRC)43, COPD Assessment Test (CAT)44.

* Pulmonary function referring to how well a lung works and commonly measured by, for example spirometry and peak flow meter to test the forced expiratory volume in 1 second (FEV1) or peak expiratory flow rate respectively.

* Quality of Life defined as a multidimensional evaluation of a person sense of well-being, encompassing physical, psychological, social and spiritual dimensions,45 which measured by, for example the Medical Outcomes Study Short Form (SF-36)46, Asthma Quality of Life Questionnaire (AQLQ)47, St. George Respiratory Questionnaire (SGRQ)48,49.

* Health service utilization due to exacerbation of respiratory symptoms, including:

(a) Emergency department visits: defined as urgent consultation to hospital emergency department.

(b) General practitioners visits: defined as planned or unplanned consultation to general practitioners or family physicians.

(c) Hospitalizations: defined as admission to hospital.

Types of studies

This systematic review will include randomized controlled trials (RCTs). In the absence of RCTs, other research designs such as non-randomized or quasi-experimental studies and clinical trials without control groups will be considered in this review. Observational studies, case studies, descriptive studies, literature reviews, systematic reviews, clinical guidelines or recommendations, editorials or reports of expert opinions will be excluded. Studies which are not written in the English or Chinese languages will be excluded.

Search strategy

The search strategy aims to identify both published and unpublished studies in English and Chinese. A three-step approach will be adopted. Firstly, a limited search of MEDLINE and CINAHL will be performed with identification of keywords followed by analysis of the text words used in the title and abstract, and of the index terms used to describe relevant articles. Second, an extensive search of all included databases will be performed using all identified keywords, index terms and matched subject headings. As index terms and matched subject headings vary in each database, individual search strategies will be established for each database. Finally, hand searching of other sources of studies, including a manual search of relevant respiratory journals such as Chest, Thorax and Respiratory Medicine, conference proceedings from organizations such as Asian Pacific Society of Respirology (APSR), European Respiratory Society (ERS), and the American Thoracic Society (ATS) and postgraduate and doctoral dissertations, online search of databases and websites such as Google Scholar will be undertaken to retrieve additional articles that are not located through the search strategies. Reference lists of all relevant articles will be screened in an effort to reveal additional potential studies.

The English databases to be searched will include:

Academic Search Premise (1975-present), British Nursing Index (1994-present), CINAHL Plus (1937-present), Cochrane Central Register of Controlled Trials (CENTRAL), Educational resources Information Center (ERIC) (1980-present), EMBASE (1980-present), Global Health, Health Sciences: A SAGE Full-Text Collection (1982-present), International Pharmaceutical Abstracts (IPA) (1970-present), MEDLINE (1950-present), ProQuest Health & Medical Complete, ProQuest Research Library: Health & Medicine (1971-present), PsycArticles, Psychology: A SAGE Full-Text Collection, PsycINFO (1806-present), ScienceDirect, Scopus (1823-present).

The Chinese databases to be searched will include:

China Journal Net (CJN) Symbol 1915-present, Chinese Biomedical Literature Database (CBM) Symbol (1978-present), Chinese Medical Current Contents (CMCC) SymbolSymbol (1994-present), HyRead Symbol 1974- present, Taiwan Electronic Periodical Services (TEPS) Symbol, Hong Kong Index to Chinese Periodical HKInChiP (Symbol) (1980-present), WanFang Data Symbol

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The databases to be searched for unpublished studies or grey literature will include:

Academic Archive Online, Agency of Healthcare Research and Quality, Althealth Watch, Digital Dissertations, Dissertation Abstracts International, Grey Literature Report (via New York Academy of Medicine), Index to Theses, Lancashire Care Library and Information Service, MEDNAR, National Library of Medicine Gateway, Netting the Evidence, The Networked Digital Library of Theses and Dissertations

The initial English keywords to be searched will include:

* Concept 1: Chronic respiratory disease* or chronic respiratory tract disease* or chronic respiratory disorder* or chronic lung disease* or chronic pulmonary disease* or tracheobronchial disease* or the list of common chronic respiratory diseases involving the use of inhalation drug therapy published by WHO in 2007 (including asthma, bronchi?etasis, chronic obstructive pulmonary disease, chronic obstructive airway disease, COPD, COAD, bronchitis, emphysema) or wheez* or short* of breath or SOB or dyspn?ea

* Concept 2: Inhal* therapy or aerosol* therapy or inhal* adj6 administration or metered adj6 inhaler* or dry powder inhaler* or inhaler*

* Concept 3: Adherence or compliance or cooperation or concordance

* Concepts 4: Inhal* technique or inhal* flow or self administration or clinical competence

* Concepts 5: education or training or teaching or counsel?ing or self management or self-management or self?monitoring or psychotherapy or psychosocial therapy or psycho education or psycho-education or cognitive therapy or behavio?r* therapy or behavio?r intervention* or reminder system* or reinforcement.

The initial Chinese keywords to be searched will be

Assessment of methodological quality

The methodological quality of the included studies will be assessed by two reviewers independently prior to inclusion using the standardized critical appraisal instruments from the Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) for randomized controlled/ pseudo-randomized trial (Appendix I). Disagreements between the reviewers will be resolved through discussion, or with a third reviewer.

Data collection

Data of the included studies will be extracted by using the JBI-MAStARI data extraction form (Appendix II). Two reviewers will extract data independently for assurance of data accuracy. Discrepancies between the reviewers will be resolved by discussion or where resolution is not successful, by a third reviewer. The data extracted will include precise details about the populations and participant characteristics, inclusion and exclusion criteria, study settings and designs; descriptions of interventions, outcomes measures and results, and the number and reasons for withdrawal and dropout. If there is any data missing in the included studies, the authors will be contacted to retrieve statistical data if possible.

Data synthesis

The included studies will be categorized according to the type of interventions being conducted. All results will be subjected to double data entry to minimize the risk of errors. Effect measures expressed as odds ratio or relative risks (for dichotomous data), mean differences (for continuous data collected using the same scale) and standardized mean differences (for continuous data collected using different scales) and their 95% confidence intervals will be calculated and used as the summary measures of effects. If appropriate, quantitative results of comparable studies will be pooled in statistical meta-analysis using JBI-MAStARI. Clinical heterogeneity, statistical heterogeneity and publication bias of the included studies will be examined following the meta-analysis.

Clinical heterogeneity of the studies will be assessed by considering the settings, populations, interventions and outcome measures. Statistical heterogeneity of the combined studies will be assessed using the Chi-square test. A fixed effects model will be applied for pooling if there is no clinical or statistical heterogeneity; while a random effects model will be used in the absence of clinical heterogeneity but with the presence of statistical heterogeneity. Publication bias will be evaluated by using a funnel plot.

Additional analysis such as sensitivity analysis and subgroup analysis will be performed. Sensitivity analysis exploring the impact of studies with high risk of bias will be performed to assess the robustness of the pooled results. Subgroup analyses will also be conducted to evaluate the comparisons between one type of educational intervention and other types of interventions, different designs of interventions including components, modes and intensities of interventions and different intervention providers. If statistical pooling of results of the included studies is not possible, the findings will be presented in narrative form.

Conflicts of interest

No conflict of interest.

Acknowledgements

We would like to thank Professor Kai Chow CHOI, Professor Doris YU, Professor Janita CHAU and Professor Iris LEE for their valuable advice on development of this protocol.

References