ANALYSIS OF INFLUENTIAL FACTORS OF MEDICATION ADHERENCE OF INHALATION DEVICES IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE

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1 Acta Medica Mediterranea, 2018, 34: 1703 ANALYSIS OF INFLUENTIAL FACTORS OF MEDICATION ADHERENCE OF INHALATION DEVICES IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE ZHIYING WANG Department of Respiratory, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang , China ABSTRACT Introduction: The objective of this study was to investigate influential factors of medication adherence of inhalation devices in patients with chronic obstructive pulmonary disease (COPD)through the following criteria: application scores of the inhalation devices, physician effective guidance, the number of acute exacerbation, adverse drug reactions (ADRs). Materials and methods: A total of 130 patients with COPD who sought medical care in the hospital were recruited for the study. Questionnaire survey was performed to evaluate medication adherence of inhalation devices. The obtained data were analyzed by using a t-test, a Chi-square test, and a binary logistic regression analysis to determine the relationship of the above various factors with medication adherence. Then, the 130 patients were randomly divided into an intervention group and a control group. The intervention group was interviewed by the physician in the process of using inhalation devices. After 3 months and 6 months, observed the difference of the two groups. Results: The analysis indicated that there was a close relationship between medication adherence of inhalation devices and the following criteria: application score of the inhalation devices, ADRs, the number of acute exacerbations, and effective guidance of physicians. Compared with the control group, application scores of the inhalation device of the intervention group were significantly improved. The number of acute exacerbation decreased by 16%, the incidence of ADRs in the intervention group was 13.6% lower than that in the control group, and the difference was statistically significant. Conclusion: After physician effective guidance, the application scores of the inhalation devices were improved, the number of acute exacerbation and ADRs decreased. Physician should take intervention measures in accordance with the influential factors of medication adherence of inhalation devices to improve treatment efficacy of COPD Keywords: chronic obstructive pulmonary disease (COPD), inhalation device, medication adherence, influential factor. DOI: / _2018_6_260 Received January 30, 2018; Accepted March 20, 2018 Introduction Chronic obstructive pulmonary disease (COPD is a common disease characterized by continuous constrained airflow which becomes progressively worse but can be prevented and treated. It is caused by toxic gas particles in the airway and lungs or enhanced by chronic inflammation. COPD is the fourth leading cause of death among the deadly diseases in the world. The World Health Organization (WHO) predicts that chronic lung disease will be the third leading cause of death worldwide by 2020.The WHO recently held a series of campaigns to call on the world to pay attention to COPD: the silent killer. As people gain a deeper understanding of lung function and lung diseases such as chronic lung disease, people realize that inhaling medicine is the simplest and most effective way to treat these diseases (1, 2). At present, the most frequent inhalation drug delivery systems (IDDS) are pressurized metered dose inhalers (PMDIs) and dry powder inhalers (DPIs) (3), such as Tiotropium Bromide Powder for inhalation, Salmeterol Xinafoate and Fluticasone Propionate Powder for inhalation, and Budesonide and Formoterol Fumarate Powder for inhalation, etc. Most lung conditions of patients can be controlled well by using appropriate medication. Medication adherence refers to the degree of compliance of the patient with the drug treatment.

2 1704 Zhiying Wang The low level of medication adherence is an important effect of bad treatment results. Therefore, it is very important to improve patient medication adherence to control chronic airway disease. Compared to patients who have no symptoms and who have evident symptoms, their compliance is significantly different in the therapeutic effect (4). The low compliance of COPD patients with the use of inhalation is influenced by patient factors such as age, education, income, health insurance, etc. There are also some factors related to the disease and medication: the recognition range of the disease, the validity of the application of inhalation device, and the number of cases, the categories of medicine, the adverse reactions of drugs (5), etc. At present, there are few articles researching the compliance of using inhalation devices for COPD patients. This research analyzes COPD patient compliance on the inhalation device andinfluential factors. It will provide a reference for improving the effect of inhalation therapy. Materials and methods We selected outpatients and inpatients with COPD from the respiratory department of our hospital from January 2015 to December Inclusion criteria: Match condition with the Global Strategy for Diagnosis, Management, and Prevention of COPD (updated) issued by the Global Initiative for Chronic Obstructive Lung Disease; Age ranging from 35 to 75 years old; The course of disease should be greater than 1 month, using the inhaled medicine device; Basic literacy and communication skills. Exclusion criteria: COPD combined with other trachea, bronchial and pulmonary diseases; COPD combined with severe heart, liver, or renal insufficiency and neurological or mental illness; The results were not observed properly due to the deterioration of the disease. There were 130 patients in the study, including 75 outpatients and 55 inpatients; 68 males and 62 females. Their age was from 35 to 75 years old, and the average was 59.3±6.1 years old. The patients using Tiotropium Bromide Powder for inhalation (business name SiLiHua), Salmeterol Xinafoate and Fluticasone Propionate Powder for inhalation (business name ShuLiDie), and Budesonide and Formoterol Fumarate Powder for inhalation (business name name XinBiKe) were 34, 21, and 47 respectively. Twenty-eight patients used two or more inhalation devices. All patients gave informed consent We used a questionnaire survey to evaluate the following content: the patient's age, literacy, health insurance, marital status, smoking, drinking, the number of physicians consultations, ADRs, the compliance of inhalation device, and application scores of the inhalation device. It took about 5 minutes to investigate each patient. The 130 patients were divided into an intervention group and a control group according to random sample number method. There were 65 cases per group. There was no statistically significant difference between the two groups in age, sex, health care, culture, and number of devices. The medication adherence of inhalation devices was evaluated by using a questionnaire survey. The contents of the questionnaire included the general situation of the patient, the condition of the disease, the situation of the medication, the degree of understanding of the disease, and the expected intervention paths. We scored by the evaluation standard of compliance in patients with anti-hypertension therapy (CPAT), using Morisky-Green (MG) standard (6). The following four questions should be proposed and the score should be established relative to them: When the disease is under control, whether to stop the medicine or reduce the quantity yes (1 point), no (2 points); How do you handle it when your condition worsens: use medicine that you choose 1 point), change medicine by yourself (1 point), add medicine by yourself (1 point), or go to hospital to see a doctor (2 points); Whether to take the medicine according to the prescribed time yes (2 points), no (1 point); Whether to take the medicine according to the prescribed category and quantity: yes (2 points), no (1 point). Finally, we accumulated the scores. More than 8 points was good CPAT, less than 8 was bad CPAT. Evaluation form of theinhalation devices was graded by patient s operation of inhalation devices. The methods of using DPIs are divided into 10 steps and evaluated respectively. It includes sitting straight, opening and filling the device, exhaling,

3 Analysis of influential factors of medication adherence of inhalation devices in patients with chronic clenching the device, inhaling, holding breath, repeating, cleaning, rinsing. If each step operates correctly, patients will get one point, and the total score range is from 0-10 points. Physician intervention In the intervention group, patients were instructed by the physician to use the inhalation device and they were provided a list of the steps of the procedure. To understand the importance of proper use of inhalation devices and to motivate the patients to use devices, physicians explained the theoretical disease-related knowledge, and the methods of mitigation, control, monitoring, and routine protection to the patients. After that, physicians intervened by phone and reminded them of the medication days and the remaining dose, and they regularly check the patient s inhalation device scale window. The control group was scored by the physician according to the score sheet and provided the operation steps, and the physician did not intervene with the patients. After 3 months and 6 months after intervention, the device usage scores, adverse reactions, and exacerbation of the intervention group and the control group were retrospectively analyzed. Among them, 3 patients were lost in the intervention group and 5 patients were lost in the control group. Statistical analysis All analyses were performed using computer software SPSS17.0. Descriptive statistics are presented as mean ± standard deviation.categorical variablesare presented as percentage. To make compliance as dependent variable, a single factor analysis was performed on the relevant factors (t test or χ2 test); variables that have significance in single factor analysis will be analyzed by a binary logistic regression analysis. A p<0.05 was accepted as the level of statistical significance for all tests. Results Survey results of inhalation device adherence According to CPAT s evaluation criteria, of the 130 patients who were examined by questionnaires, 58 patients (44.6 %) appropriate use of the inhalation device (total score 8), 72 patients (55.4%) demonstrated poor adherence (total score < 8). Single variable analysis of the factors influencing the adherence of inhalation devices The clinical data of the patients, application scores of the inhalation device, the ADRs, the incidence of acute exacerbation, and the degree of physician intervention are shown in Table 1. It shows that the adherence of inhalation devices was significantly correlated with application scores of the inhalation device, the ADRs, the number of acute exacerbation, and the degree of physician intervention. Binary logistic regression analysis of the factors influencing the adherence of inhalation devices In the binary logistic regression analysis, we selected four factors of the above mentioned to enter the regression equation. The results showed that the above four factors were still obviously related to the adherence of inhalation devices (Table 1). The patients with low scores when using inhalation devices, low physician intervention, more ADRs, and the high number of acute exacerbation, demonstrated poor adherence of inhalation devices. Analysis of reason for the low score when using the devices Regarding device compliance, we found that poor compliance was mainly manifested as incorrect gargling or no use of mouthwash (55%), lack of breath-holding or insufficient breath-holding time (53%). The results are shown in Table 2. Comparison of the application scores of inhalation devices between the intervention group and the control group Before intervention, the intervention group had no significant difference compared with the control group in the score of using devices (P> 0.05). It had significant difference compared with the control group at 3 months and 6 months after the intervention (P <0.05). The intervention group had significant difference at 3 months and 6 months after the intervention compared with pre-intervention (P <0.01), however the control group had no statistically difference at 3 months and 6 months after the intervention compared with pre-intervention (P> 0.05). The results are shown in Table 3.

4 1706 Zhiying Wang Influencing factor Good adherence (n=58) Bad adherence (n=72) Singlefactor analysis of χ2 value and P value Age (year) 58.6± ±5.5 P=0.674 Gender male female Health insurance yes no p> p>0.05 Binary logistic analysis of P values The incidence of acute exacerbation 2 The difference of acute exacerbation in the intervention group at 6 months after the intervention was statistically significant compared with preintervention (P<0.05). After the intervention, the difference between the intervention group and the control group was statistically significant (P<0.05). The number of episodes of acute exacerbation ( 2 times) in the intervention group decreased by 16% compared with the control group (Table 4). Error type Number of patients Percentage % Incorrect gargling or no mouthwash Literacy Illiterate and primary school High school and above The number of inhalation device Marital status p> p> p>0.05 Lack of breath-holding or insufficient breath-holding time Absence of exhaling or incorrect exhaling Forgetting to clean the device Can t open the devices correctly Can t charge correctly 10 8 Clench devices incorrectly 8 6 Married Incorrect sitting position 4 2 Unmarried/divorced/ widowed Smoking p>0.05 Table 2: Patient wrong performance of inhalation device and its proportion before intervention. no 8 10 yes Intervention time Intervention group (n=62) Control group (n=60) Drinking p>0.05 Pre-intervention 5.98± ±1.54 no After 3 months 8.79±0.561) 2) 6.55±1.32 yes Application scores of the drug inhalation devices 6.8± ±2.1 P=0.023 p<0.05 P=0.031 ADRs p<0.01 P=0.019 yes 8 25 no In 1 year, the acute exacerbation number 2 yes no p<0.01 P=0.027 After 6 months 9.18±0.661) 2) 6.87±0.49 Table 3: Comparison of application scores of inhalation devices in intervention and control group. Note: 1) P <0.01, there is significant statistical difference after the intervention compared with the pre-intervention; and 2) P <0.05, the intervention group compared with the control group was statistically significant. Intervention time Intervention group n=62 Control group n=60 Pre-intervention 42% 39% Physicians guidelines (intervention 3 times) yes no p<0.01 P=0.037 Table 1: COPD patients influential factors in medication adherence of inhalation devices. Note: ADRs:adverse drug reactions After 3 months 29% 36% After 6 months 18%1) 2) 34% Table 4: Comparison of the proportion of acute exacerbation 2 in intervention and control group. Note: 1) P <0.05, there is significant statistical difference after the intervention compared with the pre-intervention; and 2) P <0.05, the intervention group compared with the control group was statistically significant. Degree of adverse reactions There were 18 cases of adverse reactions

5 Analysis of influential factors of medication adherence of inhalation devices in patients with chronic among 122 patients in the intervention period. There were 5 cases in the intervention group, and 13 cases in the control group. After six months, the incidence of adverse reactions in the intervention group decreased by 13.6% (P <0.05) compared with the control group (P<0.05). The difference was statistically significant. The results are shown in Table 5. Adverse reaction Discussion Intervention group (n=62, 8.1%) palpitation 1 oral ulcer 1 Inhalant And Formoterol budesonide inhalation powder Control group (n= %) The development of the DPIs represented a substantial forward step in the evolution of the inhalation strategy: they do not contain propellants and they optimize inhaled drug consistency and the extent of its lung deposition. Also they generally minimize the role of patient s cooperation and comprehension in limiting the effectiveness of inhalation (7, 8). However, because of various factors, the use adherence of inhalation devices of patients with COPD was not high. We will discuss the influential factors which we found in the study that were closely related to inhalation devices medication adherence. Application scores of the drug inhalation device By the study of the structure characteristics, usage methods, and precautions of the common inhalers, we divided the operation of the inhaler into 10 steps. It includes sitting straight, opening and filling the device, exhaling, clenching the device, inhaling, holding breath, repeating, cleaning, and rinsing. Mastering methods and skills of exhaling are the basis of evidence-based management for continuous chronic airway disease (9). 2 4 Inhalant And Formoterol budesonide inhalation powder thirst 2 Tiotropium bromide 4 Tiotropium bromide hoarseness 1 Budesonide formoterol 3 And Budesonide formoterol Table 5: Comparisonthe type and inhalantof ADRs in intervention and control group. Note: ADRs:adverse drug reactions The curative effect of inhalation drugs is often influenced by deposition of drug particles in the different parts of the respiratory tract, inspiratory speed, and epithelial cell infiltration. Many incorrect operation steps can lead to adverse reactions and attenuation. For example, if patients do not exhale or exhale well before taking medicine, does not holding breath or the hold time is not enough after taking medicine, or does not wash mouth deeply, the lung deposition rate will reduce and the throat deposition rate will increase. Poor sitting posture can cause anteflexion of trachea or tracheostenosis, increase the suction resistance and hinder inhalation of drugs. The correct inhalation method is keeping the head vertical and leaning back a little to maximize airway flow to prepare for the inhalation. After taking the drug, the saliva on the device will not only increase the moisture in the nozzle, and reduce the amount of the powder, but it will also shorten the service life of the device. The correct operation should be to use a clean cloth to wipe the remaining saliva. The occurrence of adverse reactions and weakening of efficacy will directly affect the patient medication adherence. So, using the inhalation device correctly has a great influence on patient medication adherence. This experiment also confirmed that the application score of inhalation devices is a factor in medication adherence. The relationship between the medication adherence of inhalation device and the frequency of effective guidance for medication from physician In the past, physician directed COPD patients with medication guidance only once, or directly let patients take medicine by instructions. This can't help the COPD patients fully master the use of the inhalation device. In addition, the following are the important factors which affect the compliance of patients with inhalation: disease knowledge about COPD, motivation of use, inhalation technology, and medication self-efficacy. Especially regarding the motivation of use, it plays an important role in changing patient behavior. Therefore, the physicians should repeatedly explain and demonstrate device operation steps. They also should motivate and encourage patients to change their behaviors of using inhalation device. Finally, the purpose of improving the compliance of patients with inhalation device will be

6 1708 Zhiying Wang achieved (10-12). This study confirmed that effective physician guidance and intervention for 3 or more times will increase patient compliance. It is the important influential factors of medication adherence. After 3-6 months of effective intervention, the application score of inhalation devices was significantly increased, the adverse reaction was reduced, and the number of acute exacerbation decreased. The relationship between the medication adherence of the inhalation devices and adverse reactions Adverse reactions are often related with pharmacological effects of drugs and incorrect use of inhalation devices. For example,anticholinergicswill cause thirst, and receptor agonists will cause increased heart rate, palpitations, hand shaking, and headache. In addition, improper use of inhalation devices usually leads to adverse reactions. If patients do not wash mouth deeply after taking the medicine, do not exhale or do not exhale long enough, or swallow mouth wash into the gastrointestinal tract, they will get throat candida infection, hoarseness, sore throat, and other bad responses. The occurrence of adverse reactions can affect the patient medication adherence and curative effect. Proper use of inhalation devices may reduce adverse reactions. By rinsing the mouth immediately after taking the medication, the patient can remove the drug from the mouth and pharynx. At the same time, deep exhalation can reduce the water vapor in the oral cavity and respiratory tract and reduce the residual drug in the larynx or other parts, thereby improving the deposition rate at the effective site. The relationship between the medication adherence of inhalation device and the frequency of acute exacerbation Melani (13) found that patients who do not know how to use or incorrectly use the inhalation device would stop the treatment because of bad therapeutic effects. It can lead to an increase in the number of acute exacerbations. It is reported that patient drug inhalation compliance is positively correlated with control rate (14). Some researchers found that some patients cannot open the device properly. They only rotated the dose spring one time and opened the dust cap only, or did not open the dose valve. Some of the patients cannot exhale properly, or exhale toward device. It caused the water vapor to enter the device. It will dampen the powder. Some patients did not know about inhaling deeply and holding the breath for about l0 seconds after deep inhalation to ensure sufficient amount of the drug to reach the predetermined location and reduce the occurrence of bad reactions. This bad medication adherence inevitably brings about the acute exacerbation of the disease. The living habits and forgetfulness of patients (especially elderly patients) are also important causes of the increased number of acute exacerbations. Patients cannot fully grasp the application method of the device by the one-time-only medication guidance. Patients with chronic diseases tend to use more kinds of drugs. In this study, some patients used more than two inhalation devices. In cases of no effective monitoring, it is easy for them to alternate or skip the medication. Conclusion This study found that the compliance of inhalation devices is related to adverse reactions, the number of acute exacerbations, the application score of inhalation devices, and the effective guidance of physicians. However, it is not related to the patient's age, gender, education, marital status, medical insurance, possession of devices, smoking, or drinking. Correct use of inhalation devices and effective physician guidance can improve patient compliance with inhaled medication and reduce the incidence of adverse reactions and acute exacerbation. Improving compliance with inhalation devices is significant for managing chronic disease of COPD patients, which can effectively improve the treatment effect and improve the prognosis of patients. References 1) Celli BR, MacNee W, Agusti A, AnzuetoA, BergB,et al. Standards for the diagnosis and treatment of patients with COPD a summary of the ATS ERS position paper. Eur Respir J 2004; 23 (6): ) Seville PC, LI HY, Learoyd TP. Spray-Dried Powders for Pulmonary Drug Delivery. Crit Rev Ther Drug Carrier Syst2007; 24 (4): ) Lavorini F, Corrigan CJ, Barnes PJ, DekhuijzenPRN, LevyML, et al. Retail sales of inhalation devices in European countries: So much for a global policy. Respir Med2011; 105 (7): ) Lasmar L, Camargos P, Champs NS, Fonseca MT, FontesMJ, et al. Adherence rate to inhaled corticosteroids and their impact on asthma control. Allergy2009; 64(5):

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