臺灣博碩士論文加值系統

研究背景:
至今心血管相關疾病仍為死亡的主因之一，因此對於預防此類疾病的發生已成為相當重要的課題。許多研究顯示statins類藥品不僅可有效降低血脂，更可用於預防心血管疾病的發生率。然而越來越多研究指出statins藥品順從性與預防心血管疾病發生之臨床療效具高度相關性，發現到低順從性者相對於高順從性者其死亡率可高出8%。其中影響服藥順從性的因素包含對於statins藥品的認知、其本身收入以及醫療人員與使用者之間的互動等等。就國內來說，statins屬於高價藥品，於健保支出中占有越來越大的比例，因此在國內全民健保制度下，患者使用statins的順從性如何?以及順從性與心血管疾病發生率的關係是值得加以探討的議題。
研究目的:
探討statins藥品持有率與預防心血管疾病之相關性
研究方法:
本研究之研究設計為回溯性世代研究，資料來源主要以2000~2004年健保資料庫，ATC/DDD system；研究對象針對2001年於醫學中心首次發生心血管相關疾病住院患者(index date)，且於出院後90天內處方statins者；以持有率做為順從性代表，持有率定義:持有率=(statins總處方天數/一年追蹤天數)x100%，持有率分為三等級80%:high，79~40%:medium，<40%:low，Endpoint則定義為再次發生心血管疾病而住院。
研究結果:
依照病患所發生心血管疾病分為冠心病組，以及缺血性中風組，各自計算病患一年藥品持有率，將病患分為三等級後各組病患依序為:冠心組，藥品持有率高者:1196人，藥品持有率中者:1170人，藥品持有率低者:1414人；中風組:藥品持有率高者:412人，藥品持有率中者:604人，藥品持有率低者:908人；而各組其心血管疾病再發生率依藥品持有率高至低為，冠心病組:22.91%，30.26%，29.68%；中風組:4.48%，14.22%，54.24%。將藥品持有率與心血管疾病再發生率做存活分析後發現，在冠心病組，其藥品持有率之風險比為1.038(P=0.6085)，校正後為1.011(P=0.8836)；中風組，其藥品持有率之風險比為1.411(P=0.0001)，校正後為1.423(P<0.0001)，進一步以迴歸分析探討各自不同程度藥品持有率與心血管疾病再住院率的關係。在冠心病組，相對於高藥品持有率病患，藥品持有率中病患其風險比為1.373(P=0.0437)，校正後風險比為1.326(P=0.0755)，藥品持有率低病患風險比為1.094(P=0.5677)，校正後風險比為1.05(P=0.7521)；而中風組，相對於高藥品持有率病患，藥品持有率中者其風險比為1.562(P=0.0526)，校正後風險比為1.552(P=0.0584)，藥品持有率低者風險比為2.130(P=0.0003)，校正後風險比2.131(P=0.0004)。
研究結論:
Statins類藥品可有效降低心血管疾病再次發生率，而藥品順從性卻又是決定藥品有效與否的關鍵，本研究以藥品持有率代表藥品順從性，進一步證實，在冠心病組中，隨著順從性的增加，心血管再發生率也越低，雖然並未達到統計學上差異；而中風組，藥品順從性對於心血管疾病再發生率有一定的重要性，且藥品順從性低者相對於藥品順從性高者，其風險比例又較高，因此，如何提高藥品順從性，可說是決定病患預後的一項重要關鍵。

Background:
Until now, cardiovascular disease is still one of the major causes of death. To prevent cardiovascular disease has become an important issue. Many studies have proved that statins can not only effectively control hyperlipidemia but also help to prevent cardiovascular disease. However more and more studies have shown that the adherence of statins and cardiovascular disease prevention is highly related. The mortality of patient with low compliance is higher by 8 % than that of patients with high compliance. There are a lot of factors which may affect compliance, including the knowledge about statins, income, and the interaction between health care provider and patients. In Taiwan, statins has accouted for large part of National Health Insurance expenditure. Therefore, it is important to investagate the association between adherence of statins and cardiovascular disease.
Objective:
To analyze the association between adherence of statins and cardiovascular disease.
Method:
Our study design is a retrospective cohort study. The data source is from National Health Insurance in 2000~2004. Our subjective is patients with first cardiovascular disease in medical center used statins in 90 days after discharge.Use medication possession ratio (MPR) to present adherence, the calculation of MPR: MPR= (statins prescribed days) /365 days (365days as followed duration)x100%, define >80% as high MPR, 79~40% as moderate MPR, and <40% as low MPR. The endpoint is the readmission of cardiovascular disease
Result:
After calculating the one year MPR, in CHD group, there were 1196 persons in high MPR group, 1170 persons in medium MPR group and 1414 persons in low MPR group. And in ischemia stroke group, there were 412 persons in high MPR group, 604 persons in medium MPR group and 908 persons in low MPR group. The event rate of each group were 22.91%，30.26%，29.68% in CHD group and 4.48%，14.22%，54.24% in ischemia group. Used survival analysis to analyse the relationship between adherence of statins and readmission rate of cardiovascular disease, the hazard ratio of MPR in CHD group was 1.038 (P=0.6085), after ajustment the hazard ratio was 1.011 (P=0.8836), and the hazard ratio of MPR in ischemia stroke group was 1.038 (P=0.6085), after ajustment the hazard ratio was 1.011(P=0.8836). Furthermore our study analysed the readmission risk of different MPR by logistic regression. In CHD group, the odds ratio of moderate MPR group, compared to high MPR group, was 1.373 (P=0.0437), after ajustment the hazzar ratio is 1.326(P=0.0755), and the odds ratio group in low MPR group is 1.094(P=0.5677), after ajustment the hazard ratio was 1.05 (P=0.7521). In ischemia stroke group, the odds ratio of moderate MPR group, compared to high MPR group, was 1.562 (P=0.0526), after ajustment the hazard ratio was 1.552 (P=0.0584), and the odds ratio group in low MPR group was 2.130 (P=0.0003), after ajustment the hazard ratio is 2.131 (P=0.0004).

Conclusion:
Statins can effectively prevent readmission of cardiovascular disease. And compliance is the key point of statins’ effect. No matter in CHD group or ischemia group, the worse the compliance, the higher the risk of cardiovascular disease.

中文摘要 ........................................................................................................................... i
Abstract ............................................................................................................................ iii
誌謝 ................................................................................................................................ vi
目錄 ............................................................................................................................... vii
表目錄 .............................................................................................................................. x
圖目錄 ............................................................................................................................. xi
第一篇、高風險病人Statins類降血脂藥品持有率與其心血管疾病再發生率之相關性 1
第一章 、研究緣起 1
第二章 、文獻回顧 3
第一節 心血管流行病學 3
2.1.1心血管疾病與缺血性腦中風盛行率 3
2.1.2心血管疾病及其相關危險因子 3
第二節 高血脂流行病學 5
2.2.1高血脂盛行率 5
2.2.2高血脂與心血管疾病相關性 5
第三節 降血脂治療目標與策略 7
第四節 Statins 類降血脂藥品臨床效果 13
2.4.1降血脂效果 13
2.4.2心血管疾病預防效果 13
第五節 藥品順從性與療效 17
2.5.1影響藥品順從性之相關因子，以statins為例 17
2.5.2 Statins類藥品順從性與心血管疾病療效之關係 18
第三章 、研究目的&重要性 20
第四章 、研究方法 21
第一節 研究型態 21
第二節 研究材料 21
第三節 研究工具 22
第四節 研究對象 22
4.4.1納入對象 22
4.4.2排除條件 22
第五節 研究變項與名詞之操作定義說明 23
4.5.1研究名詞定義 23
4.5.2研究變項定義 24
第六節 研究流程 26
第七節 統計分析 31
3.7.1統計模式設定 31
3.7.2資料分析方法 31
第五章 、研究結果 32
第一節 病患基本資料 32
5.1.1病患分組流程 32
5.1.2病患之基本資料 32
第二節 分組比較基本性質與結果 35
5.2.1冠心病組其各藥品持有率組之基本性質 35
5.2.2中風組其各藥品持有率組之基本性質 36
第三節 各影響因子與心血管疾病再住院率風險比 45
第四節 藥品持有率與心血管疾病再住院率 49
5.4.1一年藥品持有率與心血管疾病再住院率 49
5.4.2敏感性測試 50
第六章 、討論 54
第一節 病患基本資料 54
第二節 Statins類藥品使用時機 57
第三節 Statins類藥品持有率 61
第四節 藥品持有率與心血管疾病及再住院率關係 63
6.4.1心血管疾病再住院率於各組間差異 63
6.4.2持有率與心血管疾病再住院率關係及其影響因子 63
第五節 與其他研究之討論 66
6.5.1藥品持有率與藥品順從性 66
6.5.2類似研究結果之比較 66
6.5.3研究設計之異同 67
第七章 、研究限制 69
第八章 、結語與建議 71
第二篇、 臨床藥事服務-高危險藥品注意事項 73
第一章 、背景 73
第二章 、目的 73
第三章 、方法 74
參考文獻 104

1.Cardiovascular diseases. WHO, 2008. (Accessed 2008, at http://www.who.int/cardiovascular_diseases/en/.)
2.台灣地區死因統計結果摘要. 衛生署統計室. (Accessed 2008, at http://www.doh.gov.tw/statistic/index.htm.)
3.National Cholesterol Education Program Expert Panel on Detection E, Treatment of High Blood Cholesterol in A. 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.[see comment]. Circulation 2002;106:3143-421.
4.Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.[erratum appears in Circulation. 2004 Aug 10;110(6):763]. [Review] [45 refs]. Circulation 2004;110:227-39.
5.Rasmussen JN, Chong A, Alter DA. Relationship between adherence to evidence-based pharmacotherapy and long-term mortality after acute myocardial infarction. Jama 2007;297:177-86.
6.Chiang CW, Chiu HF, Chen CY, Wu HL, Yang CY. Trends in the use of lipid-lowering drugs by outpatients with diabetes in Taiwan, 1997-2003. Pharmacoepidemiol Drug Saf 2007;0:0.
7.Heart Disease and Stroke Statistics -- 2008 Update (At-a-Glance Version). American Heart Association, 2008. (Accessed at http://www.americanheart.org/downloadable/heart/1200078608862HS_Stats%202008.final.pdf.)
8.Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). Jama 1986;256:2823-8.
9.Iso H, Jacobs DR, Jr., Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med 1989;320:904-10.
10.Barter P, Gotto AM, LaRosa JC, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007;357:1301-10.
11.Castelli WP. Epidemiology of coronary heart disease: the Framingham study. Am J Med 1984;76:4-12.
12.陳建仁. 台灣地區高血糖、高血脂、高血壓盛行率調查: 國民健康局; 2003.
13.Ross R. Atherosclerosis--an inflammatory disease.[see comment]. [Review] [149 refs]. N Engl J Med 1999;340:115-26.
14.Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685-95.
15.Chapman MJ. From pathophysiology to targeted therapy for atherothrombosis: a role for the combination of statin and aspirin in secondary prevention. [Review] [88 refs]. Pharmacology & Therapeutics 2007;113:184-96.
16.Talbert RL. Hyperlipidemia. In: Joseph T. DiPiro P, FCCP Robert L. Talbert, PharmD, FCCP, BCPS Gary C. Yee, PharmD, FCCP Gary R. Matzke, PharmD, FCP, FCCP Barbara G. Wells, PharmD, FASHP, FCCP, BCPP L. Michael Posey, BS Pharm, ed. Pharmacotherapy: A Pathophysiologic Approach. 6 ed: MCGRAW-HILL; 2005:429.
17.行政院衛生署國民健康局. 高血脂防治手冊-國人血脂異常診療及預防指引. 高血脂防治手冊 2003.
18.M.MacKenney J. Dyslipidemias, Atherosclerosis, and Coronary Heart Disease. In: Mary Anne Koda-Kimble P, Lloyd Yee Young, PharmD Wayne A.Kradjan, PharmD, BCPS B.Joseph Guglielmo, PharmD, ed. Applied therapeutics:the clinical use of drugs. 6 ed: Lippincott Williams & Wilkins; 2004:13-1.
19.Roberts WC. The rule of 5 and the rule of 7 in lipid-lowering by statin drugs. Am J Cardiol 1997;80:106-7.
20.Knopp RH. Drug treatment of lipid disorders. N Engl J Med 1999;341:498-511.
21.Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9.
22.Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996;335:1001-9.
23.Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349-57.
24.Anonymous. Screening experience and baseline characteristics in the West of Scotland Coronary Prevention Study. The WOSCOPS Study Group. West of Scotland Coronary Prevention Study. American Journal of Cardiology 1995;76:485-91.
25.Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. Jama 1998;279:1615-22.
26.Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. Jama 2001;285:1711-8.
27.Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.[see comment]. Lancet 2002;360:1623-30.
28.Serruys PW, de Feyter P, Macaya C, et al. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. Jama 2002;287:3215-22.
29.Officers A, Coordinators for the ACRGTA, Lipid-Lowering Treatment to Prevent Heart Attack T. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT).[see comment]. Jama 2002;288:2998-3007.
30.Sever PS, Dahlof B, Poulter NR, et al. 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.[see comment]. Lancet 2003;361:1149-58.
31.Collins R, Armitage J, Parish S, Sleigh P, Peto R. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005-16.
32.Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364:685-96.
33.Amarenco P, Bogousslavsky J, Callahan A, 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006;355:549-59.
34.de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. Jama 2004;292:1307-16.
35.LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-35.
36.Straus SE, Majumdar SR, McAlister FA. New evidence for stroke prevention: scientific review. Jama 2002;288:1388-95.
37.O'Regan C, Wu P, Arora P, Perri D, Mills EJ. Statin therapy in stroke prevention: a meta-analysis involving 121,000 patients. [Review] [69 refs]. American Journal of Medicine 2008;121:24-33.
38.Nassief A, Marsh JD. Statin therapy for stroke prevention. [Review] [27 refs]. Stroke 2008;39:1042-8.
39.Amarenco P, Bogousslavsky J, Callahan A, 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006;355:549-59.
40.Amarenco P, Bogousslavsky J, Callahan AS, et al. Design and baseline characteristics of the stroke prevention by aggressive reduction in cholesterol levels (SPARCL) study. Cerebrovasc Dis 2003;16:389-95.
41.Amarenco P, Labreuche J, Lavallee P, Touboul PJ. Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke 2004;35:2902-9.
42.O'Keefe JH, Jr., Cordain L, Harris WH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol 2004;43:2142-6.
43.LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-35.
44.World Health Organization WHO, Eduardo Sabaté. Adherence to Long-term Therapies: Evidence for Action World Health Organization; 2003.
45.Gumbs PD, Verschuren WM, Mantel-Teeuwisse AK, et al. Drug costs associated with non-adherence to cholesterol management guidelines for primary prevention of cardiovascular disease in an elderly population: the Rotterdam study. Drugs Aging 2006;23:733-41.
46.Eagle KA, Kline-Rogers E, Goodman SG, et al. Adherence to evidence-based therapies after discharge for acute coronary syndromes: an ongoing prospective, observational study. Am J Med 2004;117:73-81.
47.Simons LA, Levis G, Simons J. Apparent discontinuation rates in patients prescribed lipid-lowering drugs. Medical Journal of Australia 1996;164:208-11.
48.Ellis JJ, Erickson SR, Stevenson JG, Bernstein SJ, Stiles RA, Fendrick AM. Suboptimal statin adherence and discontinuation in primary and secondary prevention populations. Journal of General Internal Medicine 2004;19:638-45.
49.McGinnis B, Olson KL, Magid D, et al. Factors related to adherence to statin therapy. Ann Pharmacother 2007;41:1805-11.
50.Parris ES, Lawrence DB, Mohn LA, Long LB. Adherence to statin therapy and LDL cholesterol goal attainment by patients with diabetes and dyslipidemia. Diabetes Care 2005;28:595-9.
51.Colivicchi F, Bassi A, Santini M, Caltagirone C. Discontinuation of statin therapy and clinical outcome after ischemic stroke. Stroke 2007;38:2652-7.
52.高雅慧、郭垂文、洪輝榮、郭士禎. Anatomical Therapeutic Chemical (ATC) classificaton 代碼對照檔. In; 2001.
53.Cubeddu LX, Seamon MJ. Statin withdrawal: clinical implications and molecular mechanisms. [Review] [48 refs]. Pharmacotherapy 2006;26:1288-96.
54.RK K. DRUGDEX System. In: Thomson Micromedex 2008.
55.Wei L, Wang J, Thompson P, Wong S, Struthers AD, MacDonald TM. Adherence to statin treatment and readmission of patients after myocardial infarction: a six year follow up study. Heart 2002;88:229-33.
56.Benner JS, Glynn RJ, Mogun H, Neumann PJ, Weinstein MC, Avorn J. Long-term persistence in use of statin therapy in elderly patients. Jama 2002;288:455-61.
57.Huser MA, Evans TS, Berger V. Medication adherence trends with statins. Advances in Therapy 2005;22:163-71.
58.Cziraky MJ, Willey VJ, McKenney JM, et al. Statin safety: an assessment using an administrative claims database. Am J Cardiol 2006;97:61C-8C.
59.翁德昌. Statin 類降血脂藥品處方型態分析及療效可替換性評估 碩士論文: 成功大學; 2006.
60.Wolf PA, D'Agostino RB, Belanger AJ, Kannel WB. Probability of stroke: a risk profile from the Framingham Study. Stroke 1991;22:312-8.
61.Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.[see comment][erratum appears in Lancet. 2006 Oct 21;368(9545):1415; PMID: 17055933]. Lancet 2005;366:1849-61.
62.Haim M, Benderly M, Boyko V, et al. Decrease in triglyceride level by bezafibrate is related to reduction of recurrent coronary events: a Bezafibrate Infarction Prevention substudy. Coronary Artery Disease 2006;17:455-61.
63.Tanne D, Benderly M, Goldbourt U, et al. A prospective study of plasma fibrinogen levels and the risk of stroke among participants in the bezafibrate infarction prevention study. American Journal of Medicine 2001;111:457-63.
64.Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. Jama 2002;288:462-7.
65.Andrade SE, Kahler KH, Frech F, Chan KA. Methods for evaluation of medication adherence and persistence using automated databases. [Review] [22 refs]. Pharmacoepidemiology & Drug Safety 2006;15:565-74; discussion 75-7.
66.Brookhart MA, Patrick AR, Dormuth C, et al. Adherence to lipid-lowering therapy and the use of preventive health services: an investigation of the healthy user effect. Am J Epidemiol 2007;166:348-54.
67.Cheng CW, Woo KS, Chan JC, Tomlinson B, You JH. Association between adherence to statin therapy and lipid control in Hong Kong Chinese patients at high risk of coronary heart disease. Br J Clin Pharmacol 2004;58:528-35.
68.醫療服務品質. 2008. (Accessed at http://www.nhi.gov.tw/webdata/webdata.asp?menu=1&menu_id=4&webdata_id=805&WD_ID=4.)
69.Golembiewski J, Wheeler PJ. High-alert medications in the perioperative setting. J Perianesth Nurs 2007;22:435-7.
70.Treating to New Targets (TNT) Study: does lowering...[Am J Cardiol. 2004] PubMed Result. 2007.
71.Handbook on Injectable drugs 11 ed; 2001.
72.AHFS drug information. Bethesda: American Society of Hospital Pharmacists: Amer Soc of Health System; 2004.