According to WHO, medication adherence is »the extent to which a person’s behaviour – taking medication, following a diet, and/or executing lifestyle changes, corresponds with agreed recommendations from a health care provider«. Due to the characteristics of individual health conditions, medication adherence may vary significantly among groups of patients with different diseases. There may also be considerable differences between medication adherence rates in different countries because of differences in the health care system, social differences and other environmental characteristics. The literature review shows that medication adherence ranges 9% - 47% and 21% - 85% in patients with arterial hypertension and asthma, respectively. Medication adherence can be evaluated in various ways, either by direct or indirect methods. Direct methods include observation of the therapy application or measurements of plasma or urinary concentrations of active substances, its metabolites, or biological markers. Indirect methods include patient diaries, clinical response evaluations, pill count, prescription claims data analysis, use of electronic devices, and application of questionnaires. The latter are simple and low cost method to evaluate medication, and are often used in research. One of the most commonly used questionnaires is the Morisky Medication Adherence Scale (MMAS). The reasons for non-adherence are various and may be related to the characteristics of the patient, medical condition, therapy, health system or patient's socio-economic conditions. An example of a factor that can influence medication adherence is the introduction of therapeutic reference pricing system (TRP). The TRP combines comparable medicines into groups, with one medication being available without co-payment (reference medicine) and other medicines requiring a patient out-of-pocket payment of difference between the price of particular medicine and the maximum reimbursement price. Two therapeutic groups of antihypertensive medicines were introduced in Slovenia, namely angiotensin converting enzyme inhibitors (ACEi) on January 1st 2014, and angiotensin II antagonists (ARB) on September 28th 2018. The positive economic effects of TRP system have been known, but the system can have potential negative effects on patients due to more frequent changes in therapy and co-payments for medicines. The aim of the doctoral thesis is to evaluate how prevalent is medication adherence among Slovenian patients with asthma and arterial hypertension, to examine the impact of medication adherence and inhalation techniques on clinical and humanistic outcomes in asthma patients and to determine whether the introduction of TRP has a negative impact in terms of lower medication adherence and poor health outcomes in patients with arterial hypertension. For this purpose, we conducted two observational studies. The first one was a cohort study, conducted in community pharmacies. We included adult patients with hypertension who were dispensed either ACE inhibitor (ACEi) or angiotensin receptor inhibitor II (ARB). Patients with chronic kidney disease, heart failure, angina pectoris, atrial fibrillation and a history of stroke or myocardial infarction were not included in the study. We aimed at including at least 100 patients into the study, which would enable us to use a regression model with approximately 10 independent variables. At the first visit, we obtained information about patient’s antihypertensive therapy, its potential changes, and potential co-payments for antihypertensive medicines. We evaluated medication adherence with Morisky Medication Adherence Scale (MMAS-8) and measured blood pressure following a predefined protocol. After 8 weeks patient came to a follow-up visit, when we re-evaluated medication adherence by MMAS-8 and pill count as well as measured patient’s blood pressure. In the time between the first and a follow-up visit, we tried to confirm the collected data by contacting patients’ physicians. We acquired data about diagnoses (arterial hypertension and exclusion criteria), arterial hypertension therapy, and its potential changes during the pre-enrolment period and during follow up. We obtained data for 53% of patients and found 100% adherence between patients provided and physicians provided data. The second study had a cross-sectional design and was also conducted in community pharmacies. We included patients with asthma, aged 12 years or more, who were prescribed at least one medication for asthma. The sample size was calculated based on the assumption of 59% adherence, which comes from a systematic review of the literature. A total of 119 patients were required for the study, taking a 15% relative margin of error for the adherence estimation into account. We collected the data on patient demographics and duration and characteristics of their asthma therapy, and evaluated the appropriateness of inhalation technique. The inhalation technique was evaluated on the basis of the patient's use of the inhaler using check-lists of key steps of the inhalation techniques prepared for each type of inhaler, which were based on a systematic literature review. Medication adherence was evaluated with MMAS-8, asthma control with Asthma Control Test (ACT), and quality of life with Saint George Respiratory Questionnaire (SGRQ). We also collected data on acute asthma exacerbations over a one year period prior to study participation, defined as a visit to the emergency room, hospital admission, or oral glucocorticoid therapy. In order to validate patient provided data, we obtained data from medical records for 42% of patients. The data on the diagnosis of asthma, therapy and acute exacerbations of asthma were provided by physicians or pulmonologists. Diagnosis of asthma was confirmed in 90% of patients. The results of our studies show that 57%, 34% and 9% of Slovenian patients with hypertension have high, medium and low medication rate, respectively. In patients with hypertension, unintentional non-adherence is most common, as dose omissions occur mostly due to forgetfulness. Among patients with asthma, 53%, 23% and 24% have high, medium and low adherence rate, respectively. Younger patients and smokers were found to be at increased risk for non-adherence. Non-intentional non-adherence due to forgetfulness is also common among asthma patients; however, intentional non-adherence is also quite common, since the second most frequent reason for irregular medication taking in patients with asthma was feeling better and the absence of symptoms. The results of the first study show that therapy changes due to TRP are so rare that they do not represent a significant factor for non-adherence and blood pressure control. Among 114 patients enrolled in the study, there were no patients who experienced a change in therapy in order to avoid co-payment because of TRP. Thirty-nine (34%) patients were required to co-pay for their blood pressure lowering medicines. Three (2.6%) refused to co-pay and undergone generic substitution. Among patients who paid for medicines, the 44.4% co-paid for ARB and 36.1% for ACEi. Other co-payments were due to generic substitutions between different medicines containing BB (17%) or CCB (3%). The proportion of patients with prescribed ACEIs who had to co-pay was 14%, while half of the patients with prescribed ARBs co-paid for their ARB containing medicines. The average co-payment was comparable for both groups, at € 4.70 for ACEIs and € 4.88 for ARBs. Patients with co-payments had better medication adherence compared to those who were not required to co-pay. The proportion of patients with high adherence rate at the first visit was 86% in the co-payment group and 61% in the reference group. The blood pressure in the co-payment group was on average 10 mm Hg (SBP) and 4 mm Hg (DBP) higher than in the group without co-payment. A multivariable analysis showed that the difference in blood pressure between the groups was not present due to the co-payments, but due to the characteristics of the patients, namely gender or medication adherence. The results therefore show a positive effect of co-payments for antihypertensive therapy on medication adherence, whereas no effect of co-payments on blood pressure control in patients with arterial hypertension. In the second study we confirmed the association between medication adherence evaluated by MMAS-8 and asthma control as well as a health-related quality of life. Logistic regression revealed that patients with high medication adherence had 1.7-fold higher odds (odds ratio: 1.65; p = 0.027) for controlled asthma compared with those with medium medication adherence rate. The latter had 1.7-fold higher odds (odds ratio: 1.65; p = 0.027) for controlled asthma compared with those with low adherence rate. Patients with better medication adherence also had better quality of life. Linear regression showed that patients with high adherence rates had 5.3 points lower (p = 0.045), and patients with medium adherence rate had 6.1 points lower SGRQ values (p = 0.048) compared with patients with low adherence rate. On the basis of the link between medication adherence in asthma patients and their health outcomes, we established the criterion validity of the MMAS-8 questionnaire for asthma patients, which is necessary for valid classification of patients as adherent or non-adherent. Based on a proven association between mediation adherence and health outcomes we also set the new cut-off values for classification of asthma patients as adherent or non-adherent. We modified the cut-off values to distinguish between low adherence rate (≤6 points) and medium adherence rate (> 6 to ˂8 points), while the categorization of high adherence rate remained the same (8 points) as established by Morisky. The appropriateness of inhalation technique in asthma patients was evaluated for four types of inhaler devices, namely, pressure metered-dose inhalers, Turbuhaler, Twisthaler, and Diskus. The results show that the inhalation technique is inappropriate in most of asthma patients, since at least one error in handling of their inhaler device was made by 70% of the patients. Most common were errors among patients with Diskus, and least common among those with Turbuhaler. The most common inhaler type independent error was the absence of exhalation prior to initiation of inhalation, observed in 34% of the patients. The most common inhaler type dependent error was the preparation of the inhaler device. The complexity of preparation from patient's perspective differs considerably between different inhaler types. Diskus was appropriately prepared by only 15% of the patients, while the proportions of patients who prepared the inhaler correctly were much higher in the case of Turbuhaler (64%), Twisthaler (75%) and pressure metered-dose inhalers (93%). Somewhat less common, but in view of the critical impact on drug delivery to the lungs more significant mistake is to perform an insufficiently deep and inappropriately rapid inhalation. Inappropriate inhalation step was observed in 27% of patients, most often among those with pressure metered-dose inhalers (41%). The inhalation technique in patients in the study did not affect their health outcomes. With the Mann-Whitney test, we compared patients who performed the individual inhalation technique step correctly or incorrectly, but we found no statistically significant differences in asthma control between them. In addition, we ran the logistic regression model to evaluate the concomitant impact of inhalation technique and medication adherence on asthma control. We again confirmed the impact of medication adherence (odds ratio: 1.97; p = 0.039), while the impact of inhalation techniques (odds ratio: 0.98; p = 0.914) on asthma control was not shown.
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