臺灣博碩士論文加值系統

研究背景:
腦中風在已開發國家是一個相當盛行的疾病，在台灣十大死因中,2017年腦血管疾病名列第四位，統計顯示腦中風發生率約為千分之三，其中約四分之三為缺血性中風；另外依據世界衛生組織資料，2016年共造成1520萬人死亡，可見此為高度盛行的疾病。中風的生成原因很多,很多時候與生活型態有很大的關係，其中與飲食習慣偏高油導致的高血脂有很大關係，所以控制高血脂是相當重要的關鍵。
目前較為常用的降血脂的藥物為statins與non-statin lipid lowering medication(fibrates)兩大類藥品，可以有效控制血脂避免血管堵塞，其中statins可以有效避免中風的發生。然而考量健保給付在於各個statin間的給付價有差異，且statins療效比較缺乏本土性的調查，也缺乏本土性statins和fibrates療效比較關係，因此比較服用後預防發生缺血性中風再次住院的風險就顯得格外重要。
研究方法:
本研究為回溯性世代研究，資料來源為中央健康保險署2005年至2010年全民健康保險資料申報檔之全人口檔。本世代研究對象為2005-2010年被診斷有高血脂的病人，且初次因缺血性中風(Ischemic Stroke)而住院，並且有使用單一降血脂藥物90天以上，追蹤總天數365天以上。排除條件為因車禍住院、年齡小於45歲及因病危而死亡和自殺出院者。研究的事件為因缺血性中風而再次住院。本研究使用累積風險比來分析結果。
研究結果:
總共有9098人納入本次分析結果，其中statins組為8016人，non-statin lipid lowering medication組為1082人。病患中使用high intensity statin人數為6479人，low intensity statin人數為1537人，糖尿病人數為3080人，心衰竭人數為661人；statin組發生缺血性中風再次住院人數為477人，non-statin lipid lowering medication組發生缺血性中風再次住院人數為91人。COX model迴歸分析中(95%信賴區間，P值)，non-statin lipid lowering medication(fibrates)組相對low intensity statin組因缺血性中風再次住院校正風險比為1.32(0.96-1.79, p=0.054)，rosuvastatin組相對atorvastatin組因缺血性中風再次住院校正風險比(95%信賴區間)為0.64(0.50-0.87, p=0.001)，simvastatin組風險比為1.07(0.75-1.36, p=0.608)；在所有納入研究降血脂藥物中，rosuvastatin的效果最好，p值為0.001具有統計上的意義。
結論:
本研究發現在高血脂族群中,預防缺血性中風再次住院statins效果有優於fibrates趨勢，在各種statins中rosuvastatin相對atorvastatin有較低的風險。

Background:
Brain stroke is a very prevalent disease in developed countries. Among the top ten causes of death in Taiwan, cerebrovascular disease ranked fourth in 2017. Statistics show that the incidence of stroke is about three-thousandths. About three-quarters of them are ischemic strokes; according to the World Health Organization, a total of 15.2 million deaths were caused in 2016, which is a highly prevalent disease. There are many reasons for the occurrence of stroke. Many times, it has a lot to do with life style. It relates to hyperlipidemia caused by high fat dietary habits. Therefore, controlling hyperlipidemia is a very important key.
At present, the more commonly used drugs for lowering blood lipid are statins and non-statin lipid lowering medication(fibrates), which can effectively control blood lipids to avoid vascular occlusion, and statins can effectively prevent people from occurrence of stroke. However, considering the health insurance differs among a variety of statins, and the efficacy of statins relatively lacks for local investigation, what’s more, the lack of comparison between statins and fibrates matters as well. Therefore, it is particularly important to compare the risk of re-hospitalization of ischemic stroke after taking the prescribed.
Method:
This study is a retrospective cohort study, with data provided by National Health Insurance Administrations 2005-2010 national health insurance claim data for the entire population. The patients of this period from 2005 to 2010 were diagnosed hyperlipidemia, they had have been hospitalized for the first time due to ischemic stroke, and had taken a single lipid-lowering drug over 90 days, more than one year had they been tracked. Exclusion criteria were those who were hospitalized because of car accidents, were younger than 45 years old, and died of illness and suicide. The primary outcome of rehospitalization is aimed at ischemic stroke. This study used cumulative hazard ratios to analyze the results.
Result:
9098 people in total were included in the analysis, with 8016 in the statins group and 1082 in the non-statin lipid lowering medication(fibrates) group. The number of patients using high intensity statin was 6479, the number of patients using low intensity statin was 1537, the number of patients with diabetes was 3080, and the number of heart failure was 661. The number of patients with re-ischemic stroke in the statin group was 477, and in the non-statin lipid lowering medication group was 91. In the COX model regression analysis (95% confidence interval, p value), the adjusted hazard ratios of the non-statin lipid lowering medication to the low intensity statin group was 1.32(0.96-1.79, p=0.054) for the re-ischemic stroke, the risk ratio of rosuvastatin to atorvastatin was 0.64 (0.50-0.87, p=0.001) for the re-ischemic stroke, and the risk ratio for simvastatin was 1.07 (0.75-1.36, p=0.608); according to the studies of hypolipidemic drugs, rosuvastatin has the best effect, whose p value of 0.001 was statistically significant.
Conclusion:
This study revealed that there are trending statins better than fibrates to prevent patients from rehospitalization of ischemic stroke. Of all statins, rosuvastatin contains a lower risk when compared with atorvastatin.

表目錄....................................................6
圖目錄....................................................8
中文摘要.................................................10
Abstract.................................................13
第一章 研究源起..........................................15
第二章 文獻回顧..........................................17
第一節 腦血管疾病....................................17
2.1.1腦血管疾病的死因排名與花費..................17
2.1.2 腦血管疾病盛行率與發生率...................17
2.1.3 腦中風的分類...............................20
2.1.4 腦血管疾病相關危險因子.....................22
第二節 高血脂與腦中風疾病............................26
2.2.1 高血脂盛行率...............................26
2.2.2 高血脂的定義...............................28
2.2.3 高血脂與腦血管疾病的關係...................29
第三節 statins和fibrate的作用機轉和差異.............30
2.3.1 主要作用機轉...............................30
2.3.2 對於中風保護效果機轉主要差異...............32
2.3.3 statins與發炎介質的關係....................33
第四節 statins與fibrates中風保護效果之臨床試驗與研究.35
2.4.1 statins....................................35
2.4.2 fibrates...................................37
2.4.3 statins與fibrates.........................38
第三章 研究目的..........................................40
第四章 研究方法..........................................41
第一節 研究設計......................................41
4.1.1 研究架構...................................41
4.1.2 研究材料與工具.............................41
4.1.3 納入對象...................................42
4.1.4 排除條件...................................42
第二節 研究變項及操作型定義..........................44
4.2.1 研究分組定義...............................44
4.2.2 用藥持續性.................................44
4.2.3 研究終點...................................44
4.2.4 疾病共變因子...............................47
第三節 資料處理流程..................................49
4.3.1 檔案串聯...................................49
4.3.2 研究流程...................................50
第四節 統計方法......................................52
4.4.1 統計工具...................................52
4.4.2 統計結果意義...............................52
4.4.3 資料分析方法...............................52
第五章 研究結果..........................................54
第一節 基本資料......................................54
5.1.1 研究流程...................................54
5.1.2 病患基本資料...............................57
第二節 缺血性中風(Ischemic Stroke)與其影響因子的關聯.62
5.2.1 statins與缺血性中風(Ischemic Stroke)之關聯..62
5.2.2 其他影響因子與腦中風關聯性.................67
第三節 缺血性中風(Ischemic Stroke)與statin使用之次分 析.......................................................71
5.3.1次分析: 限定使用high intensity statin病人..71
5.3.2次分析: 限定糖尿病病人......................73
5.3.3 次分析: 限定無糖尿病病人...................78
5.3.4次分析: 無心衰竭(HF)及無糖尿病(DM)族群......83
5.3.5次分析: 以服藥配合度來分組..................87
第六章 討論..............................................89
第一節 基本資料......................................89
6.1.1 高血脂與腦中風.............................89
6.1.2 病患基本資料...............................90
第二節 statins/fibrates與腦中風之關聯性探討.........92
第三節 用藥配合度...................................97
第四節 研究設計討論.................................99
第七章 研究限制.........................................101
第八章 結論與未來展望...................................102

1.衛生服利部統計處，106年國人死因統計結果. 2017.
2.世界衛生組織前十位死亡原因. 2016.
3.認識腦中風 - 國泰綜合醫院. 2014.
4.Goldstein, L. B.; Adams, R.; Alberts, M. J.; Appel, L. J.; Brass, L. M.; Bushnell, C. D.; Culebras, A.; DeGraba, T. J.; Gorelick, P. B.; Guyton, J. R., Primary prevention of ischemic stroke: A guideline from the American heart association/American stroke association stroke council: Cosponsored by the atherosclerotic peripheral vascular disease interdisciplinary working group; cardiovascular nursing council; clinical cardiology council; nutrition, physical activity, and metabolism council; and the quality of care and outcomes research interdisciplinary working group: The American academy of neurology affirms the value of this guideline. Stroke 2006, 37 (6), 1583-1633.
5.台灣腦中風學會. 2008.
6.Amarenco, P.; Labreuche, J., Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. The Lancet Neurology 2009, 8 (5), 453-463.
7.Naci, H.; Brugts, J. J.; Fleurence, R.; Ades, A. E., Comparative effects of statins on major cerebrovascular events: a multiple-treatments meta-analysis of placebo-controlled and active-comparator trials. QJM: An International Journal of Medicine 2013, 106 (4), 299-306.
8.WHO top ten causes of death. 2016.
9.top ten causes of death in the USA. 2016.
10.Mozaffarian, D.; Benjamin, E. J.; Go, A. S.; Arnett, D. K.; Blaha, M. J.; Cushman, M.; Das, S. R.; de Ferranti, S.; Després, J. P.; Fullerton, H. J., Heart disease and stroke statistics-2016 update a report from the American Heart Association. Circulation 2016, 133 (4), e38-e48.
11.Feigin, V. L.; Lawes, C. M.; Bennett, D. A.; Barker-Collo, S. L.; Parag, V., Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. The Lancet Neurology 2009, 8 (4), 355-369.
12.邱弘毅, 腦中風之現況與流行病學特徵. 腦中風會訊 2008, 15 (3), 2-4.
13.台北榮民總醫院- 腦中風的簡介及其預後. 2015.
14.Adams Jr, H. P.; Bendixen, B. H.; Kappelle, L. J.; Biller, J.; Love, B. B.; Gordon, D. L.; Marsh 3rd, E., Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993, 24 (1), 35-41.
15.Investigators, S. P. b. A. R. i. C. L., High-dose atorvastatin after stroke or transient ischemic attack. New England Journal of Medicine 2006, 355 (6), 549-559.
16.Gage, B. F.; Waterman, A. D.; Shannon, W.; Boechler, M.; Rich, M. W.; Radford, M. J., Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. The Journal of the American Medical Association 2001, 285 (22), 2864-2870.
17.Global Health Observatory (GHO) data. 2008.
18.衛生福利部國民健康署國民營養健康狀況變遷調查. 2017.
19.National, C. E. P. N., 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.
20.Amarenco, P., Lipid lowering and recurrent stroke: another stroke paradox? Oxford University Press: 2005.
21.Leppälä, J. M.; Virtamo, J.; Fogelholm, R.; Albanes, D.; Heinonen, O. P., Different risk factors for different stroke subtypes: association of blood pressure, cholesterol, and antioxidants. Stroke 1999, 30 (12), 2535-2540.
22.Yaghi, S.; Elkind, M. S., Lipids and cerebrovascular disease: research and practice. Stroke 2015, 46 (11), 3322-3328.
23.Corvol, J.-C.; Bouzamondo, A.; Sirol, M.; Hulot, J.-S.; Sanchez, P.; Lechat, P., Differential effects of lipid-lowering therapies on stroke prevention: a meta-analysis of randomized trials. Archives of internal medicine 2003, 163 (6), 669-676.
24.Tirschwell, D.; Smith, N.; Heckbert, S.; Lemaitre, R.; Longstreth, W.; Psaty, B., Association of cholesterol with stroke risk varies in stroke subtypes and patient subgroups. Neurology 2004, 63 (10), 1868-1875.
25.Lindenstrom, E.; Boysen, G.; Nyboe, J., Influence of total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: the Copenhagen City Heart Study. British Medical Journal 1994, 309 (6946), 11-15.
26.Haque, T.; Khan, B. V., Atorvastatin: a review of its pharmacological properties and use in familial hypercholesterolemia. Clinical Lipidology 2010, 5 (5), 615-625.
27.Roach, A. E.; Tsikouris, J. P.; Haase, K. K., Rosuvastatin: A new HMG-CoA reductase inhibitor for hypercholesterolemia. Formulary 2002, 37 (4), 179-179.
28.Stein, E. A.; Lane, M., Comparison of statins in hypertriglyceridemia. The American journal of cardiology 1998, 81 (4), 66B-69B.
29.Tood, P.; Goa, K., Simvastatin: a review of its pharmacological properties and therapeutic potential in hypercholesterolemia. Drugs 1990, 40, 583-607.
30.Staels, B.; Dallongeville, J.; Auwerx, J.; Schoonjans, K.; Leitersdorf, E.; Fruchart, J.-C., Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998, 98 (19), 2088-2093.
31.Donnan, G. A.; Davis, S. M., Stroke and cholesterol: weakness of risk versus strength of therapy. Stroke 2004, 35 (6), 1526-1526.
32.Rosenson, R. S.; Tangney, C. C., Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. The Journal of the American Medical Association 1998, 279 (20), 1643-1650.
33.Amarenco, P.; Labreuche, J.; Lavallée, P.; Touboul, P.-J., Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke 2004, 35 (12), 2902-2909.
34.Di Napoli, M.; Schwaninger, M.; Cappelli, R.; Ceccarelli, E.; Di Gianfilippo, G.; Donati, C.; Emsley, H. C.; Forconi, S.; Hopkins, S. J.; Masotti, L., Evaluation of C-reactive protein measurement for assessing the risk and prognosis in ischemic stroke: a statement for health care professionals from the CRP Pooling Project members. Stroke 2005, 36 (6), 1316-1329.
35.Collaboration, E. R. F., C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. The Lancet 2010, 375 (9709), 132-140.
36.Plehn, J. F.; Davis, B. R.; Sacks, F. M.; Rouleau, J. L.; Pfeffer, M. A.; Bernstein, V.; Cuddy, T. E.; Moyé, L. A.; Piller, L. B.; Rutherford, J., Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) study. Circulation 1999, 99 (2), 216-223.
37.Sever, P. S.; Dahlöf, B.; Poulter, N. R.; Wedel, H.; Beevers, G.; Caulfield, M.; Collins, R.; Kjeldsen, S. E.; Kristinsson, A.; McInnes, G. T., Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. The Lancet 2003, 361 (9364), 1149-1158.
38.Wang, D.; Liu, B.; Tao, W.; Hao, Z.; Liu, M., Fibrates for secondary prevention of cardiovascular disease and stroke. Cochrane Database of Systematic Reviews 2015, (10).
39.Saha, S. A.; Kizhakepunnur, L. G.; Bahekar, A.; Arora, R. R., The role of fibrates in the prevention of cardiovascular disease—a pooled meta-analysis of long-term randomized placebo-controlled clinical trials. American heart journal 2007, 154 (5), 943-953.
40.Jun, M.; Foote, C.; Lv, J.; Neal, B.; Patel, A.; Nicholls, S. J.; Grobbee, D. E.; Cass, A.; Chalmers, J.; Perkovic, V., Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. The Lancet 2010, 375 (9729), 1875-1884.
41.Rubins, H. B.; Robins, S. J.; Collins, D.; Fye, C. L.; Anderson, J. W.; Elam, M. B.; Faas, F. H.; Linares, E.; Schaefer, E. J.; Schectman, G., Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. New England Journal of Medicine 1999, 341 (6), 410-418.
42.Rosenson, R. S., Current overview of statin-induced myopathy. The American journal of medicine 2004, 116 (6), 408-416.
43.Noé, J.; Portmann, R.; Brun, M.-E.; Funk, C., Substrate-dependent drug-drug interactions between gemfibrozil, fluvastatin and other organic anion-transporting peptide (OATP) substrates on OATP1B1, OATP2B1, and OATP1B3. Drug metabolism and disposition 2007, 35 (8), 1308-1314.
44.Tobert, J. A., Efficacy and long-term adverse effect pattern of lovastatin. The American journal of cardiology 1988, 62 (15), J28-J34.
45.Wiklund, O.; Angelin, B.; Bergman, M.; Berglund, L.; Bondjers, G.; Carlsson, A.; Linden, T.; Miettinen, T.; Ödman, B.; Olofsson, S.-O., Pravastatin and gemfibrozil alone and in combination for the treatment of hypercholesterolemia. The American journal of medicine 1993, 94 (1), 13-20.
46.Kyrklund, C.; Backman, J. T.; Neuvonen, M.; Neuvonen, P. J., Gemfibrozil increases plasma pravastatin concentrations and reduces pravastatin renal clearance. Clinical Pharmacology & Therapeutics 2003, 73 (6), 538-544.
47.Graham, D. J.; Staffa, J. A.; Shatin, D.; Andrade, S. E.; Schech, S. D.; La Grenade, L.; Gurwitz, J. H.; Chan, K. A.; Goodman, M. J.; Platt, R., Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. The Journal of the American Medical Association 2004, 292 (21), 2585-2590.
48.Ballantyne, C. M.; Davidson, M. H., Possible differences between fibrates in pharmacokinetic interactions with statins. Archives of internal medicine 2003, 163 (19), 2394-2395.
49.Investigators, F. S., Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. The Lancet 2005, 366 (9500), 1849-1861.
50.Geng, Q.; Ren, J.; Chen, H.; Lee, C.; Liang, W., Adverse events following statin–fenofibrate therapy versus statin alone: A meta‐analysis of randomized controlled trials. Clinical and Experimental Pharmacology and Physiology 2013, 40 (3), 219-226.
51.Binbrek, A. S.; Elis, A.; Al-Zaibag, M.; Eha, J.; Keber, I.; Cuevas, A. M.; Mukherjee, S.; Miller, T. R.; Group, D. A. S., Rosuvastatin versus atorvastatin in achieving lipid goals in patients at high risk for cardiovascular disease in clinical practice: A randomized, open-label, parallel-group, multicenter study (DISCOVERY Alpha study). Current therapeutic research 2006, 67 (1), 21-43.
52.Lablanche, J.-M.; Leone, A.; Merkely, B.; Morais, J.; Alonso, J.; Santini, M.; Eha, J.; Demil, N.; Licour, M.; Tardif, J.-C., Comparison of the efficacy of rosuvastatin versus atorvastatin in reducing apolipoprotein B/apolipoprotein A-1 ratio in patients with acute coronary syndrome: results of the CENTAURUS study. Archives of cardiovascular diseases 2010, 103 (3), 160-169.
53.Nicholls, S. J.; Ballantyne, C. M.; Barter, P. J.; Chapman, M. J.; Erbel, R. M.; Libby, P.; Raichlen, J. S.; Uno, K.; Borgman, M.; Wolski, K., Effect of two intensive statin regimens on progression of coronary disease. New England Journal of Medicine 2011, 365 (22), 2078-2087.
54.Pitt, B.; Loscalzo, J.; Monyak, J.; Miller, E.; Raichlen, J., Comparison of lipid-modifying efficacy of rosuvastatin versus atorvastatin in patients with acute coronary syndrome (from the LUNAR study). The American journal of cardiology 2012, 109 (9), 1239-1246.
55.Zhong, P.; Wu, D.; Ye, X.; Wu, Y.; Li, T.; Tong, S.; Liu, X., Secondary prevention of major cerebrovascular events with seven different statins: a multi-treatment meta-analysis. Drug design, development and therapy 2017, 11, 2517.
56.Kim, J.; Lee, H. S.; Nam, C. M.; Heo, J. H., Effects of statin intensity and adherence on the long-term prognosis after acute ischemic stroke. Stroke 2017, 48 (10), 2723-2730.