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Disclaimer 약학 석사학위 논문 안지오텐신 전환 효소 억제제 개시 이후 진해제의 사용 분석 Use of Antitussives After the Initiation of Angiotensin-Converting Enzyme Inhibitors 2017년 8월 서울대학교 대학원 약학과 사회약학전공 권 익 태 안지오텐신 전환 효소 억제제 개시 이후 진해제의 사용 분석 Use of Antitussives After the Initiation of Angiotensin-Converting Enzyme Inhibitors 지도교수 홍 송 희 이 논문을 권익태 석사학위논문으로 제출함 2017년 4월 서울대학교 대학원 약학과 사회약학전공 권 익 태 권익태의 석사학위논문을 인준함 2017년 6월 위 원 장 (인) 부 위 원 장 (인) 위 원 (인) Abstract Use of Antitussives After the Initiation of Angiotensin-Converting Enzyme Inhibitors Ik Tae Kwon Department of Social Pharmacy College of Pharmacy, Seoul National University Background Angiotensin-converting enzyme inhibitors (ACEI) can induce a dry cough, more frequently among Asians. If healthcare professionals fail to detect coughs induced by an ACEI, patients are at risk of getting antitussives inappropriately instead of discontinuing ACEI. The purpose of this study was to examine how the initiation of ACEI affects the likelihood of antitussive uses compared with the initiation of Angiotensin Receptor Blocker (ARB) and to determine the effect of the antitussive use on the duration and adherence of therapy in a Korean population. Method This study is a retrospective analysis of the Korean National Health Insurance Service (KNHIS) National Sample Cohort (NSC) 2002-2013. Adult patients who were initiated with ACEI or ARB in 2004-2012 were selected. The ACEI group and the ARB group were matched by the propensity score. The covariates that can affect the likelihood of antitussive treatment were identified using the Andersen’s behavioral model of health services utilization. A multivariate logistic regression was used to assess the likelihood of antitussive use after the initiation of ACEI and the likelihood of hospital switching. The difference in duration of ACEI therapy was tested using a t-test. The difference in ACEI therapy adherence, which was measured by prescription days covered, were tested using the chi-squared test. Results A total 19,793 patients who were initiated with ACEI in 2004-2012 were matched with 39,586 patients who were initiated with ARB in in the same period. The initiation of ACEI was significantly associated with the likelihood of antitussive treatment (OR 2.241; 95% CI 2.142-2.345). In terms of the type of hospitals where the ACEI was initiated, the likelihood of the hospital switch is significantly lower for primary than tertiary hospitals (OR 0.069; 95% CI 0.057-0.083). However in terms of hype of hospitals where the antitussives were first prescribed after the ACEI initiation, the primary hospitals were significantly more associated with the hospital switching than tertiary hospitals (OR 26.806; 95% CI 21.173-33.937) The patients who were treated with antitussives after the ACEI initiation were on ACEI therapy longer than those who did not use antitussives (mean ± SD 117.9 ± 80.4 days vs. 112.0 ± 84.6 days; p < 0.001). The long-term ACEI therapy adherence was lower in patients with antitussive use than those without antitussive use (46.1% vs. 49.5%, p = 0.012). Conclusion This study found that the cough patients who were initiated with ACEI are often treated symptomatically with antitussives in Korea, instead of discontinuing ACEI. The antitussive treatment decreased the ACEI therapy adherence. A preventive approach from inappropriate prescription of antitussives secondary to ACEI-induced cough would be necessary. Key words : Angiotensin-Converting Enzyme Inhibitor, Cough, Antitussive Student number : 2015-23175 Table of Contents I. Introduction ··································································································· 4 II. Literature Review ························································································ 6 1. ACEI-induced Cough ············································································ 6 2. Korean National Health Insurance Service National Sample Cohort ········································································································ 7 III. Method ·········································································································· 10 1. Study Design and Subjects ····························································· 10 2. Measurements ······················································································· 13 3. Statistical Analysis ·············································································· 17 IV. Result ············································································································ 19 1. Antitussive Treatment after ACEI or ARB initiation ·············· 19 2. Hospital Switching ··············································································· 23 3. The effect of the antitussive use on ACEI therapy ·············· 28 V. Discussion ···································································································· 29 VI. Conclusion ··································································································· 34 VII. Reference ····································································································· 35 VIII. 국문 초록 ······································································································· 39 - 1 - Table of Contents (Tables) Table 1. Composition of the Korean National Health Insurance Service National Sample Cohort ·········································· 9 Table 2. ATC Codes and Generic Names of ACEI and ARB ····· 11 Table 3. ATC Codes and Generic Names of Antitussives ·········· 14 Table 4. Diagnostic categories of Charlson Comorbidity Index and Corresponding ICD-10 Codes ····································· 16 Table 5. Characteristics of the ACEI and ARB initiators ··········· 19 Table 6. Multivariate Logistic Regression Model for Antitussive Use after ACEI/ARB Initiation ············································· 22 Table 7. Characteristics of the patients who switched and did not switch hospitals ································································ 24 Table 8. Multivariate Logistic Regression Model for Hospital Switching ····················································································· 26 Table 8. ACEI Therapy Duration and Adherence ·························· 28 - 2 - Table of Contents (Figures) Figure 1. Structure of the National Health Insurance Program in Korea ······················································································· 8 Figure 2. Structure of the Korean National Health Insurance Service National Sample Cohort ········································· 9 Figure 3. Screening, Inclusion, and Follow up Periods ·············· 10 Figure 4. Flowchart of the Study Subject Selection Process ··· 12 Figure 5. Andersen’s Behavioral Model and Utilized Variables ···················································································· 13 - 3 - I. Introduction Angiotensin-Converting Enzyme Inhibitor (ACEI) is used as a primary drug in many chronic diseases, especially in hypertension, heart failure, and chronic kidney disease, by inhibiting the Renin-Angiotensin-Aldosterone System (RAAS) (Brugts et al., 2009). The incidence of ACEI-induced adverse drug reactions was reported to be lower than that of other cardiovascular drugs, but the most common side effect of ACEI is a dry cough, which is known to be the major cause of poor tolerability (Israili & Hall, 1992). The incidence of ACEI-induced cough is about 5-20% among Western populations, but is two times higher among Asians (Woo KS & Nicholls, 1995; Na et al., 2000; Ng & Goh, 2014). It was reported that ACEI-induced cough usually occurs within 4 weeks after the drug initiation although it may be delayed up to 6 months (Israili et al., 1992). The symptom resolves within several weeks after the discontinuation of the drug (Israili et al., 1992). Therefore, instead of using antitussives for the cough, most medical guidelines that were revised in the early 2000s, including the JNC-7 hypertension guidelines, 2005 ACCF/AHA heart failure guidelines, and 2004 KDOQI chronic kidney disease guidelines recommended to switch to Angiotensin II Receptor Blocker (ARB) which has similar mechanism of action with a much lower rate of cough compared to ACEI (Chobanian et al., 2003; Hunt et al., 2005; Kidney Disease Outcomes Quality Initiative, 2004). In Korea, a previous study reported that the incidence of ACEI-induced cough in Koreans is 40.1% with a significant risk factor of female gender (Na et al., 2000). Since the primary care physician system is not present in Korea, patients in Korea often switch their physician (Shin et al., 2011); for example, if a patient - 4 - with newly prescribed ACEI visits a physician other than the original ACEI prescriber such as otolaryngologist due to a cough, the physician will find it difficult to determine whether the patient is suffering from a simple acute upper respiratory infection such as a common cold or a side effect caused by ACEI. Therefore it is expected that the rate of cough misdiagnosis and inappropriate antitussive prescription