臺灣博碩士論文加值系統

背景：冠心病是在台灣造成死亡及罹病的主要原因，而高血脂症則是造成冠心病的重要危險因子。Statins，因為安全且可以有效降低血脂，而成為最常被處方的降血脂藥品。隨著statins的使用量日益增加，及越來越多的statins進入市場，statins間的療效相等性及安全性益顯重要。但是，目前僅有少數文獻比較不同statins在不同劑量下的降血脂效果及安全性是否相同。此外，在大型臨床試驗發表後，statins在許多國家的使用均產生變化，但在臺灣statins使用現況，目前的瞭解仍有限。
目的：透過系統性文獻回顧，評估不同statins是否具有療效相等性，以提供臨床決策者作為使用及調整藥品之參酌。並利用2000∼2004年健保資料庫，觀察statins處方型態及趨勢，以瞭解statins使用情況。
方法：在系統性文獻回顧部分，本研究從奧瑞岡州資料庫（1966-2004）、Medline（2005-2006四月）、EMbase（2005-2006四月）及Cochrane Controlled Trials Registry（2006第一季）搜尋statins的對等比較隨機研究。動物實驗、非使用原始數據的著作、研究期間小於4週及非中、英文文獻均予以排除。收納的文獻均以事先擬定的效度評估表來評定效度，並依樣本數加權後計算各藥物在不同劑量下的平均降血脂值。在處方型態分析上，由中央健保局所提供之未抽樣健保申報資料，利用健保給付藥品ATC（Anatomical Therapeutic Chemical）代碼對照檔與國際疾病傷害及死因分類標準ICD-9CM（International Classification of Diseases, 9th version, Clinical Modification）及SAS統計軟體來篩選及分析。藥品耗用劑量以每日定義日劑量（Defined Daily Dose, DDD）來表示。計算各年度各statins處方頻次、耗用劑量及金額，並依病患性別、年齡、醫院層級及就醫科別分層計算。門診資料進一步分析每日處方日劑量（prescribing daily dose, PDD）及用藥連續性（以藥品擁有率（medication possession rate）來計算）。
結果：在系統性文獻回顧方面，總計收納75篇statins對等比較研究與140個statins配對組合。經綜合所有研究數據後發現，下降低密度脂蛋白的劑量相等性為： rosuvastatin、atorvastatin 20mg以上及simvastatin 80mg可降低LDL達40％；atorvastatin 10mg、fluvastatin 80mg、lovastatin 40/80mg及simvastatin 20mg可降低30-40％LDL；fluvastatin 40mg、lovastatin 10/20mg 、pravastatin 20/40mg及simvastatin 10mg可降低20-30％LDL。在心血管保護作用及嚴重副作用方面，由於對等比較的文獻較少且發生率低，因此缺乏足夠的證據予以比較。而健保資料庫分析結果，statins處方頻次、耗用劑量及金額有逐年成長的趨勢，尤以atorvastatin為最。Statins使用族群集中於45-75歲（70％），門診病患以女性居多，住院病患則相反。除了lovastatin外，statins主要在醫學中心使用，主要就醫科別則為心臟血管內科、內分泌科及內科。雖然statins的處方逐年增加，但是對於冠心病高危險族群其使用率依然低於二成。Statins常見處方日劑量很集中，並與其單位含量相符。PDD/DDD的比值，除了lovastatin與pravstatin，大部分的statins均大於1。在停藥規定廢除後，statins使用連續性增加，而以2004年的資料來看，若以用藥連續性大於80％定義為具服藥順從性，則有轉換statins服藥順從性較沒有轉換組高28％（相對風險 1.28；95％信賴區間 1.27-1.29）。雖然統計結果顯示選用不同statins與用藥連續性等級有關，但大體而言，除了lovastatin外，其他statins用藥連續性等級均相似。
結論：Statins在特定劑量下，對於下降低密度脂蛋白的能力具有療效相等性，但是在心血管保護作用及副作用的比較上，仍有待進一步研究證實。雖然statins的使用在臺灣逐年增高，但在高風險族群的使用率依然偏低。由於大部分statins常見處方日劑量的降血脂效果相當，且使用連續性也相似，因此如果病患治療效果不佳或不能耐受，可考慮轉換其他療效相當的statins，以使statins能持續使用。

Background: Hypercholesterolemia is an important risk factor of coronary heart disease (CHD), which is the leading cause of mortality and morbidity in Taiwan. Statins are the most commonly prescribed agents for hypercholesterolemia because of their efficacy and tolerability. As the number of patients in need of statins therapy continues to increase and more statins are available on the market, information regarding the relative efficacy and safety of statins is required for decision making. However, only a few studies have directly compared the effects of different statins at various doses. In the past few years, the results from several large clinical trials have changed the utilization of statins in many countries. Little has been known about ours.
Objectives: Our first objective was to evaluate the therapeutic equivalence of statins by using systematic review. The second was to investigate the utilization and trend of prescribing patterns of statins from year 2000 through 2004 by using National Health Insurance (NHI) claims databases.
Methods: In the systematic review, a literature search of statins head-to-head randomized trials was performed with Oregon State database (1966-2004)、Medline (2005-2006.4)、EMbase (2005-2006.4) and the Cochrane Controlled Trials Registry (first quarter of 2006). Studies that were non-human, not based on primary data, with a duration of less than 4 weeks, and not published in English or Chinese were excluded. Study quality was graded with predetermined criteria, and weighted by sample size to obtain the average cholesterol reduction effect of different statins at various doses. In the drug utilization, we obtained the non-sampled NHI claims databases from the Bureau of National Health Insurance. The Anatomical Therapeutic Chemical (ATC) 7-digit coding system, International Classification of Diseases, 9th version, Clinical Modification (ICD9-CM) codes and SAS 9.1.3 software were used as the interface for extracting and analyzing the pharmaceutical claims data. The consumption of pharmaceutical products was defined by Defined Daily Dose (DDD). The prescribing frequency, consumption, and amount of statins was calculated in each year and stratified by patient’s age/sex, hospital level and physician speciality. We further analyzed prescribing daily dose (PDD) and continued rate (measured by medication possession rate) of statins based on outpatient data.
Results: For systematic review, seventy-five head-to-head studies and 140 paired comparisons on efficacy and safety between statins were extracted. Aggregated results on equivalent doses to reduce the low density lipoprotein cholesterol (LDL) indicate that fluvastatin 40mg, lovastatin 10/20mg, pravastatin 20/40mg or simvastatin 10mg could reduce 20-30% LDL, and atorvastatin 10mg, fluvastatin 80mg, lovastatin 40/80mg or simvastatin 20mg could decrease 30-40% LDL. The only two statins that can reduce LDL over 40% were rosuvastatin and atorvastatin at a dose of 20mg or more. We were unable to compare reliably the long-term cardiovascular outcomes due to the lack of sufficient head-to-head comparisons among different statins at equivalent doses. Also, the data were not sufficient to determine the relative safety between statins. For the drug utilization, statins prescribing increased over time, especially atorvastatin. Most of the patients who used statins were between 45-75 years old. In outpatient settings, most of the statin users were female, while it is the reverse in inpatient settings. Except for lovastatin, most statins were prescribed in medical centers by cardiovascular, endocrine and internal medicine physicians. Although the statin prescribing has been increasing, still only less than 20% of the cardiovascular disease high risk population has used the medication. The PDDs were more highly concentrated around a specific dose which rough equals to the strength of a statin product. The PDD/DDD ratios were over 1 in most statins, except for lovastatin and pravstatin. The continued rate of statins increased after the restriction to use lipid lowering agents was lifted by NHI. By analyzing the data of 2004, it was found that the compliance rate increased 28% for patients who switched statins (relative risk, 1.28; C.I. 1.27-1.29), where compliance was defined as having a continued rate over 80%. Though the statistics showed that level of continued rate was associated with different statins, they are generally similar except lovastatin.
Conclusions: Several statins are therapeutically equivalent in reducing LDL at specific doses. The comparison of cardiovascular outcomes and safety profiles remains to be uneventful due to the scarcity of head-to-head comparative studies on side effects and the low statistical power of most studies to detect serious side effects. Although the usage of statins increased, the prescribing rate was still low in high risk population. Because most statins had similar lipid lowering effect and continued rate at the PDD, switching to other statins with therapeutic equivalent dose might maintain/increase the continued rate when the previous therapy fails to achieve the goal or is not tolerable by the patient.

第一篇、Statins類降血脂藥品處方型態分析及療效可替換性評估 1
第一章、研究緣起 1
第二章、文獻回顧 4
第一節、高血脂定義與分類 4
2.1.1 高血脂定義 4
2.1.2 高血脂的分類 5
第二節、流行病學 7
2.2.1 高血脂盛行率 7
2.2.2 高血脂與其他疾患之關係 7
第三節、生理病理機轉 9
2.3.1 脂質代謝生理機轉 9
2.3.2 脂質代謝病理機轉 10
2.3.3 高血脂致病機轉 11
第四節、治療目標與策略 14
2.4.1 治療目標 14
2.4.2 治療策略 18
第五節、Statins類降血脂藥品的臨床效果 20
2.5.1 降血脂效果 20
2.5.2 心血管疾病預防效果 20
第六節、Statins類降血脂藥品成本效益考量 23
2.6.1 Statins類降血脂藥品使用現況 23
2.6.2 各健康保險體系管控statins使用的策略 25
第七節、Statins類降血脂藥品療效可替換性 30
2.7.1 Statins替換性研究 30
2.7.2 美國奧瑞岡州---Statins系統性文獻回顧 34
第八節、Statins類降血脂藥品-藥品使用評估 36
第三章、研究目的＆重要性 40
第四章、研究方法 41
第一節、療效可替換性評估—系統性文獻回顧 41
4.1.1 設定研究問題 41
4.1.2 文獻搜尋 42
4.1.3 搜尋策略 43
4.1.4 文獻選擇 44
4.1.5 文獻效度評估 45
4.1.6 資料收集 46
4.1.7 資料彙整&分析 46
第二節、Statins類降血脂藥品處方型態分析—健保資料庫分析 47
4.2.1 研究材料 47
4.2.2 研究工具 47
4.2.3 研究對象 47
4.2.4 研究變項及操作定義說明 48
4.2.5 研究流程 50
第五章、研究結果 54
第一節、系統性文獻回顧結果 54
5.1.1 文獻搜尋結果 54
5.1.2 收納文獻基本資料 55
5.1.3 不同statins在不同劑量下控制血脂效果 58
5.1.4 不同statins預防心血管疾病效果 70
5.1.5、不同statins產生肌病變或肝臟毒性之比較 70
第二節、健保資料庫分析結果 72
5.2.1 申報檔案概況分析 72
5.2.2 檔案基本分析 73
5.2.3 Statins使用族群分析 75
5.2.4 Statins處方型態分析 79
5.2.5 依不同性別分析statins處方型態 84
5.2.6 依不同年齡分析statins處方型態 84
5.2.7 依不同醫院層級分析statins處方型態 85
5.2.8 依不同就醫科別分析statins處方型態 88
5.2.9 Statins每日日劑量分佈 89
5.2.10 Statins使用連續性變化 91
第六章、討論 93
第一節、Statins療效可替換性評估 93
6.1.1 降血脂效果相等性 93
6.1.2 預防心血管疾病比較 96
6.1.3 副作用發生率 97
第二節、Statins處方型態分析 99
6.2.1 Statins耗用變化 99
6.2.2 Statins耗用成長原因討論 102
6.2.3 病患特性對statins處方的影響 105
6.2.4 醫院層級及就醫科別對statins處方的影響 106
6.2.5 Statins處方日劑量 107
6.2.6 Statins處方連續性 109
第七章、研究限制 111
第八章、結論與建議 113
參考文獻 116

第二篇、臨床藥事服務—高血脂病患衛教 126
第一章、衛教背景 126
第一節 高血脂藥品服藥順從性 126
第二節 如何改善服藥順從性 127
第三節 藥師在增進高血脂藥品服藥順從性的角色 128
第二章、衛教目的 129
第三章、衛教進行方式 129
第四章、衛教結果 139
第一節、衛教結果分析 139
4.1.1 基本資料分析 139
4.1.2 高血脂相關疑問分析 141
第二節、高血脂用藥相關問題 142
4.2.1 藥品特性相關問題 142
4.2.2 服藥方式相關問題 144
4.2.3 藥品副作用相關問題 149
4.2.4 藥品作用相關問題 150
4.2.5 其他高血脂相關問題 152
第五章、心得與討論 155
參考文獻 157
附錄一、高血脂衛教單冊內容 207
附錄二、降血脂藥品衛教單張 211
附錄三、門診民眾高血脂衛教投影片 221
附錄四、系統性文獻回顧收納文獻（含證據表及內在效度評估表） 226

表目錄
第一篇、Statins類降血脂藥品處方型態分析及療效可替換性評估
表2.1、Fredrickson-Levy-Lees 高脂蛋白血症分類 5
表2.2、美國國家膽固醇教育計畫NCEP-ATPⅢ血脂分類 6
表2.3、造成續發性高血脂的原因 6
表2.4、脂質代謝病理機轉 10
表2.5、NCEP-ATPⅢ依不同冠心病風險分級之低密度脂蛋白目標值 15
表2.6、10年冠心病風險評估表 16
表2.7、歐洲冠心病預防聯合任務專案小組建議血脂控制目標 17
表2.8、臺灣國民健康局高血脂治療目標 17
表2.9、不同種類降血脂藥品比較表 19
表2.10、Statins大型臨床試驗的心血管保護效果 22
表2.11、各國對於statins使用之規範 29
表2.12、Statins藥動性質比較 32
表2.13、現有statins替換具有學名藥statins之研究 33
表4.1、文獻搜尋策略 43
表5.1、收納文獻配對組合基本資料 56
表5.2、不同劑量statins降低LDL及升高HDL效果對照表 60
表5.3、不同劑量statins降低TG及達到血脂控制目標比率效果對照表 61
表5.4、Statins降低LDL效果綜整性分析結果 66
表5.5、各statins副作用發生率之比較（％） 71
表5.6、2000∼2004年健保申報檔案概況 72
表5.7、門診使用statins族群性別分佈 76
表5.8、門診使用statins族群年齡分佈 76
表5.9、住院使用statins族群性別分佈 77
表5.10、住院使用statins族群年齡分佈 77
表5.11、門診使用statins族群疾病別分佈 78
表5.12、住院使用statins族群疾病別分佈 78
表5.13、各年度門診statins品項數 80
表5.14、各年度住院statins品項數 80
表5.15、各年度門診statins處方頻次 81
表5.16、各年度住院statins處方頻次 81
表5.17、各年度門診statins耗用劑量（DDD） 82
表5.18、各年度住院statins耗用劑量（DDD） 82
表5.19、各年度門診statins耗用金額（元） 83
表5.20、各年度住院statins耗用金額（元） 83
表5.21、Statins常見每日處方日劑量分佈 90
表5.22、2004年有無轉換statins使用連續性等級比較 92
表5.23、2004年未轉換組各statins使用連續性等級比較 92
表6.1、Statins療效相等劑量表---奧瑞岡州及美國退伍軍人協會 94
表6.2、各statins在不同劑量下LDL變化值 95
表6.3、臺灣與OECD各國降血脂藥品耗用劑量比較 101
表6.4、各statins FDA核准及健保給付時間 101
表6.5、門診statins使用人數、處方頻次、劑量、金額年增率 104
表6.6、門診各statins處方頻次、耗用劑量、金額年增率 104
表6.7、各statins健保給付價格比較 106
表6.8、各statins常見處方日劑量、療效相當劑量及定義日劑量 108

第二篇、臨床藥事服務—高血脂病患衛教
表1、使用降血脂藥品病患（或民眾）疑問統計表 138
表2、衛教對象基本資料 139
表3、不同statins在不同劑量降低低密度脂蛋白的效果比較 143
表4、Statins早晚服藥時間點對降血脂效果比較 145
表5、高血壓藥品對血脂的影響 148
表6、衛生署核准具降血脂作用健康食品整理表 153

附表目錄
附表1、門診用藥金額佔率 163
附表2、住院用藥金額佔率 164
附表3、門診藥品申報概況（依ATC分類） 165
附表4、住院藥品申報概況（依ATC分類） 166
附表5、門診申報檔案族群性別分佈 167
附表6、門診申報檔案族群年齡分佈 167
附表7、住院申報檔案族群性別分佈 168
附表8、住院申報檔案族群年齡分佈 168
附表9、門診申報檔案族群疾病別分佈 169
附表10、住院申報檔案族群疾病別分佈 169
附表11、各年度門診statins處方頻次（依性別分析） 170
附表12、各年度住院statins處方頻次（依性別分析） 171
附表13、各年度門診statins耗用劑量（依性別分析） 172
附表14、各年度住院statins耗用劑量（依性別分析） 173
附表15、各年度門診statins耗用金額（依性別分析） 174
附表16、各年度住院statins耗用金額（依性別分析） 175
附表17、各年度門診statins處方頻次（依年齡分析） 176
附表18、各年度住院statins處方頻次（依年齡分析） 178
附表19、各年度門診statins耗用劑量（依年齡分析） 180
附表20、各年度住院statins耗用劑量（依年齡分析） 182
附表21、各年度門診statins耗用金額（依年齡分析） 184
附表22、各年度住院statins耗用金額（依年齡分析） 186
附表23、各年度門診statins處方頻次（依醫院層級分析） 188
附表24、各年度住院statins處方頻次（依醫院層級分析） 189
附表25、各年度門診statins耗用劑量（依醫院層級分析） 190
附表26、各年度住院statins耗用劑量（依醫院層級分析） 191
附表27、各年度門診statins耗用金額（依醫院層級分析） 192
附表28、各年度住院statins耗用金額（依醫院層級分析） 193
附表29、各年度門診statins處方頻次（依就醫科別） 194
附表30、各年度住院statins處方頻次（依就醫科別） 196
附表31、各年度門診statins耗用劑量（依就醫科別） 198
附表32、各年度住院statins耗用劑量（依就醫科別） 200
附表33、各年度門診statins耗用金額（依就醫科別） 202
附表34、各年度住院statins耗用金額（依就醫科別） 204


圖目錄
第一篇、Statins類降血脂藥品處方型態分析及療效可替換性評估
圖1、臺灣-Statins健保申報金額 2
圖2.1、脂蛋白分類 4
圖2.2、血脂代謝生理病理機轉 12
圖2.3、低密度脂蛋白造成粥狀動脈硬化作用機轉 13
圖2.4、OECD各國降血脂藥品耗用量 24
圖2.5、藥品使用評估與處方及調劑之關係 39
圖4.1、檔案變項串檔及對應關係圖 52
圖4.2、使用statins族群取檔流程及資料分析架構 53
圖5.1、系統性文獻回顧搜尋流程 54
圖5.2、不同劑量statins對於血脂控制百分率（加權平均值）之比較 62
圖5.3、不同劑量statins對於血脂控制百分率（證據等級B以上）之比較 64
圖5.4、Statins降低LDL 20-30％研究綜整性分析 67
圖5.5、Statins降低LDL 30-40％研究綜整性分析 69
圖5.6、依不同醫院層級分析門診statins處方型態 86
圖5.7、依不同醫院層級分析住院statins處方型態 87
圖5.8、Statins平均每日處方日劑量/定義日劑量比值 89

第二篇、臨床藥事服務—高血脂病患衛教
圖1、門診高血脂病患轉介單 132
圖2、高血脂衛教宣傳海報 133
圖3.1、高血脂衛教海報-1 134
圖3.2、高血脂衛教海報-2 135
圖3.3、高血脂衛教海報-3 136
圖3.4、高血脂衛教海報-4 137
圖4.1、降血脂藥品使用分布 140
圖4.2、降血脂藥品使用期間分布 140
圖4.3、高血脂相關疑問佔率 141
圖5、衛生署核准健康食品標章 152

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第二部分
1.Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143-3421.
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