Inhalable medicines are the established basis of asthma and COPD management according to GINA and GOLD recommendations (3,10). Depending on the diseases’ course and severity, a proper treatment scheme of asthma/COPD should be implemented, yet still a common part of these treatments are always inhaled drugs. Those drugs are effective in reducing the respiratory symptoms and in long-term disease management. Moreover, their effects are crucial in exacerbation prevention and reduction of life-threatening incidents and mortality rate. Nonetheless, in proper management of asthma and COPD patient adherence is a greatly contributing factor (11,12). Medication adherence is considered a major factor contributing to asthma/COPD exacerbations, mortality and disease course (13,14).
According to the literature, adherence is modified by numerous factors: socio-economic (e.g. family and employment), healthcare system-related (e.g. drug information and administration), condition-related (e.g. symptoms or lack of them), drug-related (e.g. drug regimen, formulation and costs) and importantly - patient-related (e.g. level of education, mental and psychological condition, health beliefs and concerns, cognitive functions) (15–17). In particular, studies show that adherence in COPD is device-related, with the device design resulting in under- or overuse, depending on its technical characteristics (dosage counter, the possibility to load an inhalation dose without real inhalation) (18). Moreover, studies show that in asthma adherence is dependent on patient treatment beliefs and perception (19).
In order to assess the patients’ adherence, a number of methods may be implemented. These include direct (e.g. drug or biomarker blood concentration) or indirect methods (e.g. pill counts, database research, self-reports) (20). The use of e-prescription databases is subject to minimized bias in assessment of primary non-adherence, since the prescription drugs may legally only be obtained when a patient possesses a prescription and fills it at a pharmacy. Self-report measures are considered not sufficiently precise and unreliable compared to other methods. Pill or dosage counts possibly overestimate the exact doses taken, as patients may influence the amount of those left in the package (21–23). However, to properly assess the primary adherence in community setting, no other method than database search provides the most accurate data (24).
Depending on the definition, setting and methodology used, primary non-adherence to various drugs reaches different levels. In accordance to definition used in this study, it reaches a wide range on extent in different settings. An analysis performed in the USA by Rutherford et al., four important drug groups - antihypertensives, lipid-lowering agents, hypoglycemics, and antidepressants – were found to reach a mean level of 14.6% primary non-adherence (25), whereas e.g. for dermatological drugs primary non-adherence reached 24.7% (26).
Few studies have covered the issue of inhaled medications primary non-adherence. yet some examples addressing this phenomenon may be found in the literature. With an approach similar to ours, Fischer et al. analysed primary non-adherence using data from 195,930 e-prescriptions from the United States. For “asthma medications”, the primary non-adherence level reached 19.9% in adults aged 19+ and 11.4% in children. For newly prescribed drugs in this field it reached 25.1% in adults and 11.3% in children. Similarly to our approach, the authors of that study analysed only the population of patients that used the e-prescriptions. In another study, also by Fischer et al., primary non-adherence to “Antiasthmatic and bronchodilator agents” medications reached 17.9% (27,28).
A meta-analysis of 31 articles on primary non-adherence published in 2019 by Cheen et al. summarized the results of 6 studies in asthma/COPD area published in years 2009-2014. The levels of primary non-adherence to the asthma/COPD medications ranged between 9-25%, with an average of 14.0%. In comparison, for other therapeutic areas covered in this meta-analysis, the primary non-adherence reached 25.0% for osteoporosis, 16.0% for hypertension, 10.0% for diabetes, 25.0% for hyperlipidemia and 12.0% for depression (17.0% across all groups). The authors also indicated several factors significantly associated with primary non-adherence, in particular in asthma/COPD, of which positively correlated older age and male gender and higher co-payment. Interestingly, the authors did not confirm a dependence resulting from differences in dosage forms (29).
The impact of inhaler type (MDI vs DPI) on primary non-adherence has been subject only few analyses up to date. In 2014 van Boven et al. used a Dutch pharmacy dispensing data from 1994 to 2012 in order to analyse LABA persistence in COPD patients. The authors of that study found no significant differences between MDIs and DPIs (30). We believe the differences observed in our study might be a result of generally lower out-of-pocket cost of MDIs, as compared to DPIs. Of a note is that in Polish healthcare system, patients pay various drugs co-payments (with varying drug reimbursement levels: 100%, 70%, 50%, 0% or a standard co-payment of 3.20 PLN per package), that are dependent on the drug, indication, patient’s age and other.
A number of interesting results on primary non-adherence to inhaled medications have been presented in this paper. Using the data of highest possible quality available to date, that originated from a nationwide e-prescription database, a specific level of primary non-adherence to inhaled medications in Poland was proven. The non-adherence to these drugs was lower than obtained in our previous study on drivers of general non-adherence in Poland, where for drugs in 6 major areas (antidiabetic, antithrombotic, cardiovascular, cholesterol medications, antibiotics and psychiatric drugs) the primary non-adherence was 20.8% (31). Also, it was lower than of that for antihistamine drugs, for which the level of primary non-adherence was 21% (32).
Importantly, this is the very first study that covered primary non-adherence to inhaled medications in Poland and also one of the very few such studies worldwide. A certain limitation of this study came from the database structure, as it was not possible to study the exact clinical reasons of each e-prescription. The data was anonymous and no additional clinical data (in particular, the patient’s diagnosis) were available. However, this study can still be considered an objective measure of adherence in obstructive diseases, since the analysed drugs’ approved indications (as reflected in their Summaries of Product Characteristics) include only asthma and COPD management. Also noteworthy is the fact that during data collection, the new e-healthcare system Poland was a pilot solution, and this the primary non-adherence results may have been influenced. Despite that, the data used in this study is still of the highest possible quality and minimally biased. It was not self-reported nor dependent on any physicians’ opinion on patients’ non-adherence. As the lowest degree of primary non-adherence concerned patients aged 75+, the common perception of a possible technological barrier of an e-prescription system for the eldest cannot be proved. The study database originated from a nationwide pilot e-prescription programme, thus it can be considered complete.
A further study limitation was that it was only possible to analyse the primary non-adherence, that is studying the act of obtaining/not obtaining a particular e-prescription. The number of doses a patient took or skipped was also not measured. This issue could not be analysed with the data used in this study and, in fact, this was not an objectives of this study. A longitudinal analysis of a particular patient was also not possible to be performed with the analysed dataset
Finally, we could not analyse the exact reasons behind the primary non-adherence, which could have been diverse: disbelief in diagnosis or physician, , drug characteristics and other (15). We also could not analyse the impact of patients’ out-of–pocket costs (in Poland these are dependent on indication, age and having a national health insurance) on primary non-adherence, since the database did not include the data on that subject.
The use of e-prescription is rising recently, both in Europe and worldwide. Studies on e-prescription systems in Europe show their multi area benefits: health, economic, social, patient-oriented and other. Major health benefits include reduced medication errors, better medicine accessibility and, what we recognize as crucial in therapy - increased monitoring of adherence. The economic benefits include efficiency gains for healthcare professionals, better transparency, reduced frauds and printing costs. The social profits concentrate around patient satisfaction, financial relief and assistance for the elderly (33). Patients using e-prescriptions gain a possibility to trace their medication history better via a patient on-line portal. Finally, e-prescriptions help patients to adapt to other tele-health solutions, such as teleconsultations, and are of great help in case of limited physical access to healthcare facilities (e.g. recent coronavirus outbreak).
Regardless of why patients are non-adherent to inhaled medications or other drugs some corrective solutions are described. In a randomized trial of allergic rhinitis treatment with intranasal corticosteroid treatment, a daily short message service reminder improved patient adherence (34). Another SMS service for asthma patients that reminded about their daily inhaled medications was effective and increased adherence by 17.8% (35). Such an approach - an SMS reminder to obtain an e-prescription, would possibly better primary adherence. As the e-prescription solution in fact includes SMS service this approach could be simply implemented with a reminder of a particular e-prescription expiration date approaching.
A study of improving adherence to ICSs in asthma by Vollmer et al. has shown a small, yet significant improvement with an interactive voice recognition phone calls system that reminded patients of their medication refills and continuous ICS treatment. Such system, if fact similar to SMS service, could also improve primary adherence in pair with e-prescription system (36). Other approaches described in the literature include mobile apps that stress the significance of proper clinical allergy diagnosis and further encourage patients’ adherence (37–39).
In order to better picture the observed phenomenon, in our future research we intend to further broaden the analysis spectrum. This will be achieved by inclusion of higher number e-prescription databases, obtained in 2019 and further. Since from January 2020 the e-prescription is the applicable standard of drug prescribing in Poland, in near future we hope to provide even more objective and fully-nationwide results.