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系統識別號 U0026-3004201811553900
論文名稱(中文) 阿斯匹靈對於年齡相關性黃斑部病變的風險
論文名稱(英文) Risk of Aspirin Use for Age-related Macular Degeneration
校院名稱 成功大學
系所名稱(中) 臨床藥學與藥物科技研究所
系所名稱(英) Institute of Clinical Pharmacy and Pharmaceutical sciences
學年度 106
學期 1
出版年 106
研究生(中文) 李婉如
研究生(英文) Wan-Ju Lee
學號 S68001058
學位類別 博士
語文別 英文
論文頁數 112頁
口試委員 指導教授-高雅慧
口試委員-鄭靜蘭
口試委員-李中一
口試委員-林素真
口試委員-李政翰
召集委員-曾順輝
中文關鍵字 年齡相關性黃斑部病變  中風  心血管疾病  阿斯匹靈 
英文關鍵字 age-related macular degeneration (AMD)  stroke  risk factors  aspirin 
學科別分類
中文摘要 研究背景:
年齡相關性黃斑部病變 (AMD) 是先進國家裡面造成視力永久損害的第一名原因;在某些病人中,AMD進展相當緩慢,因此視力損傷會在很長的一段時間以後才發生,相對的在另外一些病人,可能單眼或是雙眼中央視力損傷卻會突然急遽的發生。隨著時間過去,這些本來模糊的地區可能變大且中央視力的空缺會慢慢進展,患有AMD的人看東西就沒有以前的銳利或是明亮。
新生血管性年齡相關性黃斑部病變 (neovascular age-related macular degeneration, nAMD) 是裡面其中一個嚴重造成視力損傷的重要類別。nAMD主要的特徵在於眼睛視網膜黃斑部下方有新生血管的生成,造成附近的小血管漏液、滲血,推擠黃斑部結構以後,形成黃斑部水腫,進而造成中央視力下降。
nAMD的致病機轉目前未明,有研究指出它可能跟視網膜脈絡膜層 (choroidal layer) 的內皮細胞增加的補體沉積物有關,許多研究指出它跟心血管疾病相關,有nAMD的患者會比較高的機率產生心血管疾病,如:中風或心肌梗塞,或是比較年輕出現AMD疾病的患者將來產生心肌梗塞的風險較高,不過這些相關性尚未有一致性的看法,故本研究會以資料庫來探討這兩者之間的相關性。
目前nAMD的治療方式雖然很多,即使最新的眼內玻璃體藥物注射 (intravitreal injection)也無法保證視力恢復,頂多只能維持住目前僅存的視力。因此探討AMD的危險因子近年來成為研究者的重要方向:除了先天遺傳因素、年齡、抽菸、種族以外,是否仍有其他因素會增加AMD的風險,例如:藥物使用。雖然亞洲人的AMD發生率比起西方人來的低,但對於藥物使用與AMD的關聯性在這幾十年來一直備受爭議。
阿斯匹靈 (aspirin) 是一個預防腦中風或其他心肌梗塞被廣泛使用的藥物,在沒有上述病史但有高風險之患者,例如:糖尿病、高血壓、高血脂的老年人,醫師會開立aspirin作為預防心血管疾病的藥物。然而aspirin會產生一些出血性的副作用,最為人所知悉就是胃出血,雖然此藥物可能可以減少心血管阻塞疾病之發生,但是對於眼部,尤其是視網膜的黃斑部,是否會跟胃出血一樣,造成AMD的發生率增加,值得探討。

研究目的:
我們想要探討新生血管性年齡相關性黃斑部病變與心血管、腦血管疾病的關係,進而研究使用阿斯匹靈的患者與沒有使用的患者,對於黃斑部病變是否有增加的風險。以下分成三個部分:
(1) AMD是否跟心血管疾病,如:中風與心肌梗塞有高度相關?
(2) 在心肌梗塞患者族群裡,使用阿斯匹靈者是否會有較高風險產生黃斑部病變?
(3) 在一般族群裡,使用阿斯匹靈的人跟沒有使用的人,兩組發生黃斑部病變風險是否不同?

研究方法:
首先本研究利用台灣健保資料庫中的百萬人抽樣檔,從2000年到2010年,選取有nAMD診斷的門診病人為研究對象,進行世代研究。指標日期 (index date) 就是在門診有nAMD診斷的日期,對照一組沒有nAMD的族群,比較兩族群產生心肌梗塞或腦中風事件的風險。接著我們從2000年到2008年,選擇患有心肌梗塞以後的患者,進行巢式病例-對照研究 (Nested Case-Control Study),其指標日期定為發生nAMD的日期,回溯比較病例組與對照組使用阿斯匹靈的時間,是否用藥越久者產生事件的風險較高。此外,我們也從2000-2013台灣健保資料庫中的百萬人抽樣檔,設定一個回溯性的世代研究,比較有使用阿斯匹靈的患者與未使用者,產生黃斑部病變的風險性。在這個研究裡面,除了應用傳統的多變項Cox回歸分析以外,亦根據傾向分數 (propensity score) 進行基本病史配對後,再比較兩個世代產生黃斑部病變的風險。

結果:
在研究的第一部分裡面,我們發現nAMD是腦中風的ㄧ個危險因子。我們所收集的931位nAMD患者,與對照組9,246人比較,在nAMD這一組裡面每1000個人年有16.25次的stroke發生率,相較於沒有nAMD這組,為11.42 (p<0.05);經過多變量分析,發現有nAMD的患者,有較高的風險產生腦中風(風險比值1.30,95%信賴區間1.01 – 1.68),其中又以出血性中風(風險比值1.70,95%信賴區間1.03 – 2.83)為主;兩組相比起來在阻塞性中風、心肌梗塞、中風加上心肌梗塞、所有死亡率等,均沒有顯著差異。
第二部分的nested case-control研究,案例組有104位,對照組有2,080位,其中以男性居多 (68.27%)。此研究將兩組使用阿斯匹靈的時間分隔成使用0.5年內、0.5-1.5年、1.5年-2.5年、大於2.5年這四個時段,在案例組 (case) 裡分別有22、25、25、32人,其對照組 (control) 裡有851、411、388、430人,我們使用logistic regression去比較case與control兩組間的勝算比,發現雖然沒有達到統計上的意義,但使用阿斯匹靈越久的時間,點估計值會越大。
第三部分的研究,研究中包括204,085位使用阿斯匹靈的患者,與478,048位沒有使用的患者相比,在aspirin使用者裡面,男性患者比例 (50.91%) 較高於女性 (49.09%);使用單變量 (univariate) 分析之後,研究中顯示出aspirin user比non-aspirin user有較高的風險產生AMD(風險比值2.85,95%信賴區間2.75 – 2.96);使用多變量 (multivariate) 分析,也是有較高的風險(風險比值2.54,95%信賴區間2.44 – 2.65)。有鑑於兩組的比較,在共病或是藥物使用史上面,都有相當大的歧異度,因此我們又採用傾向分數配對 (Propensity score matching)之方式配對兩組的共病和使用藥物,兩組各有174,129個患者,其風險比值為2.38,95%信賴區間2.25 – 2.52;接下來研究中也使用了inverse probability of treatment weighting 方法來比較兩組之風險,最後仍顯現出類似的結果(風險比值1.78,95%信賴區間1.73 – 1.82)。

結論:
本研究發現nAMD是腦中風的ㄧ個危險因子,尤以出血性中風為要。在MI之後的患者,使用阿斯匹靈者,可能發生AMD的風險比沒有使用者來的高,尤其使用時間久,風險更為明顯。相較於未使用者,阿斯匹靈使用者有較大的風險產生AMD。
英文摘要 BACKGROUND
Age-related macular degeneration (AMD) is an eye disease that has been known to lead to blindness in aged people in most developed countries. In some people, AMD progresses slowly that vision loss does not occur for a long time. On the other hand, AMD causes sudden loss of central vision in one or both eyes. Over time, the blurred area might enlarge and blank spots will develop in the central vision. Objects will not be as sharp or bright as they are used to be.
nAMD is one subtype of AMD which causes severe vision loss. nAMD is resulted from abnormal growth of choroidal vessels, which will lead to leakage of fluid or blood and swelling of macula and damage of vision.
The exact pathogenesis of nAMD is not clear yet. One study found that there was deposition of complement membrane, which attacks complex in choroidal endothelial cells and leads to macular degeneration in addition to cell apoptosis in nAMD patients. That was similar to the pathogenesis of stroke and myocardial infarction (MI). Studies found that elderly Americans with nAMD had a higher risk of cardiovascular diseases compared with patients without nAMD, which suggested that it might have common pathogenesis with cardiovascular diseases. Various studies pointed out that prior onset of AMD might have higher risks for developing cardiovascular diseases, such as MI. Therefore, we used NHIRD to examine the association of AMD and cardiovascular diseases.
Although the treatments for AMD nowadays are numerous, none can cure the disease but only reserve current vision at most. Therefore, the risk factors for AMD or its impact on other diseases have drawn attention to prevent its occurrence. Most well-known risk factors for AMD is aging, smoking, family history of AMD, and Caucasian ethnicity. Though the incidence of AMD is lower in Asians compared to Caucasians, the effect of medications on AMD is still controversial for decades.
Aspirin is one of the medications mostly prescribed in patient with previous stroke or MI for secondary prevention. Some aged people with high risks of cardiovascular events, such as diabetes mellitus, hypertension, hyperlipidemia, will be prescribed with aspirin for primary prevention as well. However, its side effects of increasing bleeding tendency, such as gastrointestinal bleeding, are highly concerned. Therefore, whether it will also induce bleeds in the abnormal vessels of AMD patients in those aged population is worth of investigation.

OBJECTIVE
The study aimed to investigate (1) the association between AMD, particularly the neovascular subtype, and stroke, myocardial infarction (MI) in Taiwan; (2) whether the longer time of aspirin use would increase the risk of AMD in post-MI patients; and (3) the impact of aspirin use on AMD compared to non-users.

MATERIALS AND METHODS
We used the Taiwan National Health Insurance Research databases (NHIRD) for the following studies. Firstly, we constructed cohorts from 2001 to 2010 of newly-diagnosed neovascular AMD patients to explore its incidence of stroke and AMI. Secondly, we used total AMI patients’ database to conduct a nested case-control study from 2000 to 2008 to estimate the odds of aspirin users to non-aspirin uses. Lastly, we assembled cohorts from 2001 to 2013 to compare the risk of AMD between aspirin users and non-aspirin users. In this study, we used Cox multivariate regression model and propensity-score matching method to compare the risk of AMD.

RESULTS
Firstly, we had identified 931 cases in the nAMD group and 9,246 cases in the comparison group. The incidence rate of all stroke events was estimated at 16.25 per 1,000 person-years and 11.42 per 1,000 person-years in the nAMD and matched groups (p<0.05), respectively, with a covariate adjusted hazard ratio (HR) of 1.30 (95% confidence interval, CI, 1.01 – 1.68). A higher risk for hemorrhagic stroke (HR, 1.70, 95% CI, 1.03 – 2.83) was also noted. No significant differences were observed in ischemic stroke, the composite of AMI/stroke, and all-cause mortality.
In the nested case-control analysis, we included 104 cases and 2,080 controls with male gender predominant (68.27%). We then divided these patients of both cases and controls into 4 groups to see the length of aspirin use on the effect of AMD, there were 22, 25, 25, 32 cases in the <0.5, 0.5 – 1.5, 1.5 – 2.5, and more than 2.5 years subgroups, respectively. And, there were 851, 411, 388, 430 controls patients in these 4 subgroups. Then we used logistic regression model to compare the odds between cases and controls. We found that the point estimate had a slightly elevation though the 95% CI didn't reach statistical significance in both unadjusted ORs and adjusted ORs.

In the third part, we included 204,085 patients in the aspirin-user group and 478,048 patients in the non-aspirin user group. Male gender (50.91%) was slightly predominant to females (49.09%) in aspirin-user group. When univariate Cox regression model was applied, the hazard ratio (HR) was 2.85 (95% CI, 2.75 – 2.96), while the multivariate Cox model showed HR, 2.54 (95% CI, 2.44 – 2.65). Then we used propensity score matching to balance the covariates between aspirin users and non-users, which included 174,129 patients in both groups, and found the HR 2.38 (95% CI, 2.25 – 2.52). After using the inverse probability of treatment weighting to further conduct regression model, the HR, 1.78 (95% CI, 1.73 – 1.82), remained higher.

CONCLUSION
Neovascular age-related macular degeneration was associated with higher risk of future stroke, especially hemorrhagic subtype. Aspirin users in myocardial infarction patients had higher risks to develop age-related macular degeneration, especially for those used for longer period. Compared to non-aspirin users, higher risks of future AMD occurrence were observed in those who had aspirin use. Physicians should be aware of these side effects and monitoring periodically, and advice patients to ophthalmic consultation when signs or symptoms of AMD incur.
論文目次 CONTENTS
Chapter 1 Introduction……………………………………………………………………1
1.1 Statement of problem………………………………………………………………….3
1.2 Specific aims…………………………………………………………………………..3
1.3 Significance of this study……………………………………………………………...5
Chapter 2 Literature Reviews…………………………………………………………….6
2.1 Introduction of age-related macular degeneration…………………………………….6
2.1.1 Classification of age-related macular degeneration………………………………..7
2.1.2 Epidemiology of age-related macular degeneration……………………………….8
2.1.3 Treatment of age-related macular degeneration update……………………………9
2.2 Relationship of age-related macular degeneration and cardiovascular diseases……..10
2.2.1 AMD versus stroke………………………………………………………………..10
2.2.2 AMD versus myocardial infarction……………………………………………….11
2.3 Mechanism of aspirin………………………………………………………………...11
2.3.1 Pros and cons of aspirin use………………………………………………………11
2.3.2 Prevention for Cardio/cerebro-vascular Diseases: what’s the Benefit-Risk Ratio..12
2.4 Impact of aspirin use in age-related macular degeneration…………………………..13
2.4.1 Aspirin versus AMD, from clinical trials…………………………………………13
2.4.2 Aspirin versus AMD, from population-based observational studies……………...14
2.5 Summary of Literature Reviews………………………………………………………14
Chapter 3 Objective and Hypothesis……………………………………………………15

Chapter 4 Method………………………………………………………………………..16
4.1 Is neovascular AMD a risk factor of cardiovascular diseases…………………….…16
4.1.1 Study Design…………………………………………………………….…..…....16
4.1.2 Data source and materials…………………………………………………..….…16
4.1.3 Study population and inclusion criteria……………………………….…..…..…..17
4.1.4 Exclusion criteria…………………………….…………………………………....17
4.1.5 Endpoint definition and censored criteria..……………………………………….18
4.1.6 Statistical analysis………………………………………………………………...18
4.1.7 Sensitivity Analysis……………………………………………………………….19
4.2 Does Aspirin Use in Myocardial Infarction Patients increases the risk of AMD…….20
4.2.1 Study Design……………………………………………………………………...20
4.2.2 Data source and materials………………………………………………………...20
4.2.3 Study population and exclusion criteria……………………..……………………20
4.2.4 Exposure definition and censored criteria ………………………………………..21
4.2.5 Statistical analysis………………………………………………………………...22
4.3 Dose Aspirin use increase the risk of AMD……………………..…………………...22
4.3.1 Study Design………………………………………………………………….......22
4.3.2 Data source and materials………………………………………………………...22
4.3.3 Study population………………………………………………………………….22
4.3.4 Inclusion and exclusion criteria…………………………………………………..23
4.3.5 Endpoint definition and censored criteria……………………………………..….23
4.3.6 Statistical analysis……………………………………………………….….….…24
4.3.7 Subgroup analysis………………………………………………………………..24
4.3.8 Sensitivity Analysis………………………………………………………..……..25
Chapter 5 Results………………………………………………………………….….….26
5.1 Is neovascular AMD a risk factor for cardiovascular diseases ……………………...26
5.2 Does Aspirin Use in Myocardial Infarction Patients increases the risk of nAMD…..27
5.3 Dose Aspirin use increase the risk of AMD…………………………..………..….…28
Chapter 6 Discussion, strength and limitations………………………..……………….30
6.1 Is neovascular AMD a risk factor for cardiovascular diseases……………………….30
6.2 Does Aspirin Use in Myocardial Infarction Patients increases the risk of nAMD......33
6.3 Dose Aspirin use increase the risk of AMD………………………..……………...…33
Chapter 7 Clinical implications and Conclusions……………………………………...38
References………………………………………………………………………………...39

INDEX OF TABLES
Table 1 Demographic and baseline characteristics of the study population………………53
Table 2 Hazard ratio of outcome variables in association with nAMD………………...…55
Table 3 Basic characteristics of cases (with nAMD event) and controls (without nAMD event)………………………………………………………………………………………56
Table 4 Number and percentage of cases and controls of aspirin users…..…...….............58
Table 5 Odds ratio of cases to controls for exposure of aspirin…………………………...59
Table 6 Demographic and baseline characteristics of the study population, aspirin users and non-aspirin users………………………………………………………………………60
Table 7 Hazard ratio and 95% confidence interval of aspirin users and non-aspirin users for AMD risks…………………………………………………………………………...…64
Table 8 Incidence of aspirin users and non-aspirin users to develop AMD, nAMD and other AMD…………………………………………………………………………………65
Table 9 Basic characteristics after PS one-to-one matching between aspirin users and non-aspirin users………………………………………………………………………………..66
Table 10 Basic information of aspirin users and clopidogrel users……………………….70
Table 11 Baseline information of aspirin users and clopidogrel users after PS one-to-one matching…………………………………………………………………………………...74
Table 12 Events of aspirin and clopidogrel users…………………………………………77
Table 13 Hazard ratio, 95% confidence interval using different models…………………78

INDEX OF FIGURES
Figure 1 Drusen ……………………………….…………....…..…………....………...….79
Figure 2 Amsler Grid……………………………………….…………..…………………80
Figure 3 Visible choroidal vessels…………………………….…………..………………81
Figure 4 Dry Age-related Macular Degeneration (AMD)…….….……….………………82
Figure 5 Neovascular AMD…………………………….…………….…………………..83
Figure 6 Algorithm of Study Cohort Selection…………….………………….……….…84
Figure 7 Kaplan-Meier survival curve of nAMD and non-nAMD groups…....….…..…..85
Figure 8 Forest plot of sensitivity analysis showing hazard ratio and 95% confidence interval…………………………………………………………………..…………………86
Figure 9 Cumulative incidence curve of Fine & Gray model……….………….…….…..87
Figure 10 Algorithm of cohort assembly……………………………….…………………88
Figure 11 Density overlay scheme before propensity score (PS) matching and after PS matching for aspirin user versus non-aspirin users…………………………….………….89
Figure 12 Density overlay scheme before propensity score (PS) matching and after PS matching for aspirin user versus clopidogrel users…………….………………………….91
Figure 13 Sensitivity analysis for aspirin and clopidogrel users…….……………………93
Figure 14 Sensitivity analysis for aspirin and no aspirin users…………….…..…………94
Figure 15 Odds ratio of different outpatient department visits……….………………..…95
Appendix I……………………………………………………………….………………..96
Appendix II……………………………………………………...………………….…….98
Appendix III……………………………………………………………………….…..…99

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