研究背景：
腦中風是一個相當令人害怕的疾病，不僅造成病患死亡，即使是存活者，也常常導致肢體障礙、意識障礙以及行為能力喪失等。世界上每年約有550萬人死於腦中風；在台灣，預估每年有1.3萬人死於腦中風。不論國內、外，腦中風始終排名在十大死因的前三位。
腦中風的危險因子包含兩大類：可改變(如：高血壓)及不可改變的危險因子(如：性別)兩大類。其中，高血壓是最主要的腦中風危險因子。大約有70%的腦中風病患本身都有高血壓的病史，因此對於預防腦中風發生，控制血壓是最重要的關鍵。
所有降血壓藥都可以藉由血壓的控制達到有效預防腦中風的發生，其中ACEI及ARB是最常用的降血壓藥之一。除了血壓的控制外，在某些臨床試驗中發現ACEI及ARB可以減少目標器官的損傷。在近期的試驗中發現，對於預防腦中風的發生，ARB似乎比起ACEI有更多的優勢。出現這種結果的原因可能來自於兩種藥品在藥理機轉上的差異。
研究目標：
比較ACEI與ARB在高血壓患者對中風預防之成效。
研究方法：
本研究為回溯性世代研究。資料來源為中央健保局資料庫1996~2006的百萬人抽樣檔。本研究之研究對象為1998~2005年間曾經被診斷為高血壓且有使用ACEI或ARB的病患。曾經中風、過去3個月曾經使用ACEI或ARB、年齡小於45歲或是同時處方ACEI和ARB者予以排除。主要研究事件為患者因為中風而住院。本研究使用存活分析方法來分析結果。

研究結果：
總共有34,203人符合納入及排除條件進入本研究；其中ACEI組有22,636人，ARB組有9,648人。兩組的糖尿病患都約佔30%，高血脂(30% vs. 38.6%) 和缺血性心臟病(26.7% vs. 33.6%)都是ARB組比較多。ACEI組中共發生了382件腦中風事件，ARB組則有144件；缺血性腦中風約佔70%。ARB組的腦中風發生比例比較低(每1000人年發生腦中風事件數：12.35vs. 9.54 )。在COX迴歸分析中，ARB組有較低的腦中風發生風險([HR] 1.35, 95% Cl 1.11-1.64)。
結論：
在本研究中發現，高血壓的族群中，相較於ACEI的使用者，ARB的使用者發生腦中風的機率下降。
本研究仍有一些限制，未來需要其他研究以證實ARB的優勢。
關鍵字：血管張力素受體阻斷劑、血管張力素轉換酶抑制劑、腦中風

Background
Stroke is a scaring disease which may cause debilitating consequences, negative impact of quality of life, a loss of independent and even death of patients. Each year, 5.5 million people die as result of a stroke across the world and about 13thousand people in Taiwan. No weather Taiwan or the whole world, stroke is the third leading death and the major health care problem.
Risk factors of stroke include nonmodifiable (sex, age, etc.) and modifiable (eg, hypertension, diabetes mellitus) factors. Of modifiable factors, hypertension is a major one and about 70% of stroke patients have it, so control of hypertension is a key point of stroke prevention.
All antihypertensive agents can reduce the risk of stroke which by the effect of blood pressure reduction and angiotensin-converting enzyme inhibitor (ACEI)/ angiotensin ll receptor blocker (ARB) are one of them usually used. According some clinical trials, the both them are effective in reducing the risk of target organ damage such as heart failure and renal failure. These kinds of effect were thought that out of blood pressure control. In recent trials, these phenomena also are found in risk reduction of stroke. In view of different mechanism of ACEI and ARB, there were a few trials to compare these two classes of drugs. The aim of this study is to compare these two classes of drugs and focus on stroke prevention.
Method
A retrospective cohort study was conducted using the Nation Health Insurance (NHI) claims database spanning the period from 1996 to 2006 representing 1 million sampling from whole population in Taiwan. The study subjects included patients who had hypertension diagnosis and initiated use of ACEI/ARB from 1998 to 2005. Those with a history of stroke, previous use of ACEI/ARB within 3 months, younger than 45 years, or received these two drugs simultaneously were excluded. The primary outcome was hospitalized due to stroke after the start of follow up. The results were analyzed using Cox proportional hazard regression.
Result
Total 32,284 patients confirmed with the inclusion and exclusion criteria in the end of study; 22,636 patients in ACEI group and 9,648 patients in ARB group. About 30% of patients have diabetes mellitus and more dyslipdemia (30% vs. 38.6%) and cardiac vascular disease (26.7% vs. 33.6%) patients in ARB group. Stroke events accounted for 382 patients in ACEI group and 144 patients in the other group, about 70% of them which were ischemia stroke. Patients receiving ARB had a lower risk for the primary outcome during follow-up (12.35 vs. 9.54 events per 1000 patient-years at risk). In COX regression model, it also show the same result (multivariable adjusted hazard ratio [HR] 1.35, 95% Cl 1.11-1.64).
Conclusion
Result of this retrospective cohort study shows that the use of ARB may reduce the risk of stroke comparing with ACEI. But some limitations were in this study, more studies were needed to prove this result.
Keywords: ACE inhibitor、ARB、stroke、hypertension、population based study

1. 衛生署統計室. 97 年台灣地區死因統計結果分析. 2009.
2. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics--2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009;119:480-6.
3. 胡漢華. 台灣腦中風防治指引. 台灣腦中風學會會訊2008.
4. Goldstein LB, Adams R, Alberts MJ, et al. 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. Circulation 2006;113:e873-923.
5. Turnbull F, Blood Pressure Lowering Treatment Trialists C. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 2003;362:1527-35.
6. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. New England Journal of Medicine 2000;342:145-53.
7. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R, Prospective Studies C. Age-specific relevance of usual blood pressure to vascular mortality: a
meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903-13.
8. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. Jama 2003;289:2560-72.
9. Blood Pressure Lowering Treatment Trialists C, Turnbull F, Neal B, et al. Blood pressure-dependent and independent effects of agents that inhibit the
renin-angiotensin system. Journal of Hypertension 2007;25:951-8.
10. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995-1003.
11. Mochizuki S, Dahlof B, Shimizu M, et al. Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a
randomised, open-label, blinded endpoint morbidity-mortality study. Lancet 2007;369:1431-9..
12. 劉嘉為. ARB 藥物於中風之預防-JIKEI 研究對國人中風預防之臨床意義. 台灣腦中風學會會訊2007;14.
13. Reboldi G, Angeli F, Cavallini C, Gentile G, Mancia G, Verdecchia P. Comparison between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk of myocardial infarction, stroke and death: a meta-analysis. Journal of Hypertension 2008;26:1282-9.
14. WHO. The top ten causes of death. World Health Organization 2004.
15. Feigin VL, Lawes CM, Bennett DA, Anderson CS. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurology 2003;2:43-53.
16. 廖建彰, 李采娟, 林瑞雄, 宋鴻樟. 2000 年台灣腦中風發生率與盛行率的城鄉差異. 台灣衛誌2006;25:223-30.
17. 邱弘毅. 腦中風之現況與流行病學特徵. 台灣腦中風學會會訊2008;15.
18. 林育德, 盧玉強, 郭弘昌, 張運德, 張鳴宏, 李介元. 高雄榮民總醫院腦中風登錄資料之分析統計. 中華醫學雜誌2002;65:307-13.
19. Adams HP, Jr., Bendixen BH, Kappelle LJ, et al. 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;24:35-41.
20. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78.
21. 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. Drugs 64 Suppl 2:43-60 2004;2:43-60.
22. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. Jama 2001;285:2864-70.

23. D'Agostino RB, Wolf PA, Belanger AJ, Kannel WB. Stroke risk profile: adjustment for antihypertensive medication. The Framingham Study. Stroke 1994;25:40-3.
24. 鄭建興, 葉炳強, 符傳孝. 不同地域華人的腦中風型態及危險因子差異：台北―紐約腦中風研究. 台灣腦中風會訊2000;7.
25. Whitworth JA, World Health Organization International Society of Hypertension Writing G. 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. Journal of Hypertension 2003;21:1983-92.
26. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet 2005;365:217-23.
27. Vasan RS, Beiser A, Seshadri S, et al. Residual lifetime risk for developing hypertension in middle-aged women and men: The Framingham Heart Study. Jama 2002;287:1003-10.
28. 陳建仁. 台灣地區高血糖、高血壓、高血脂盛行率調查. 國民健康局2003.
29. Bonny A, Lacombe F, Yitemben M, et al. The 2007 ESH/ESC guidelines for the management of arterial hypertension. Journal of Hypertension 2008;26:825;.
30. Psaty BM, Smith NL, Siscovick DS, et al. Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic review and meta-analysis. Jama 1997;277:739-45.
31. Sica DA. Angiotensin receptor blockers: new considerations in their mechanism of action. . Journal of Clinical Hypertension 2006;8:381-5.
32. Chrysant SG. Possible pathophysiologic mechanisms supporting the superior stroke protection of angiotensin receptor blockers compared to
angiotensin-converting enzyme inhibitors: clinical and experimental evidence. [Review] [71 refs]. Journal of Human Hypertension 2005;19:923-31.
33. Dahlof B. Prevention of stroke in patients with hypertension. [Review] [75 refs]. American Journal of Cardiology 2007;100:17J-24J.
34. Burnier M, Brunner HR. Angiotensin II receptor antagonists. [Review] [104 refs]. Lancet 2000;355:637-45.
35. Chrysant SG. The pathophysiologic role of the brain renin-angiotensin system in stroke protection: clinical implications. [Review] [40 refs]. Journal of Clinical Hypertension 2007;9:454-9.
36. Li J, Culman J, Hortnagl H, et al. Angiotensin AT2 receptor protects against cerebral ischemia-induced neuronal injury. FASEB Journal 2005;19:617-9.
37. Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on
cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999;353:611-6.
38. Officers A, Coordinators for the ACRGTA, Lipid-Lowering Treatment to Prevent Heart Attack T. Major outcomes in high-risk hypertensive patients
randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Jama 2002;288:2981-97.
39. Fox KM, Investigators EUtOrocewPiscAd. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study).[see comment]. Lancet 2003;362:782-8.
40. Braunwald E, Domanski MJ, Fowler SE, et al. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. New England Journal of Medicine 2004;351:2058-68.
41. Group PC. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001;358:1033-41.
42. Lithell H, Hansson L, Skoog I, et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double blind intervention trial. Journal of Hypertension 2003;21:875-86.
43. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004;363:2022-31.
44. Schrader J, Luders S, Kulschewski A, et al. Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention: principal results of a prospective randomized controlled study (MOSES). Stroke 2005;36:1218-26.

45. Pitt B, Segal R, Martinez FA, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet 1997;349:747-52.
46. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial--the Losartan Heart Failure Survival Study ELITE II. Lancet 2000;355:1582-7.
47. Dickstein K, Kjekshus J, Group OSCotOS. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet 2002;360:752-60.
48. Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. New England Journal of Medicine 2003;349:1893-906.
49. McMurray J, Solomon S, Pieper K, et al. The effect of valsartan, captopril, or both on atherosclerotic events after acute myocardial infarction: an analysis of the Valsartan in Acute Myocardial Infarction Trial (VALIANT). Journal of the American College of Cardiology 2006;47:726-33.
50. Investigators O, Yusuf S, Teo KK, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. New England Journal of Medicine 2008;358:1547-59.
51. 林銅祿. An Economic Evaluation on the Pharmaceutical Expenditure of Antihypertensive Agents in Taiwan from 1997 to 2002. 藥物食品分析2007;15.
52. Delea TE, Taneja C, Moynahan A, Thomas SK, Frech-Tamas F, Oster G. Valsartan versus lisinopril or extended-release metoprolol in preventing cardiovascular and renal events in patients with hypertension. American Journal of Health-System Pharmacy 2007;64:1187-96.
53. Urquhart J. Some economic consequences of noncompliance. [Review] [64 refs]. Current Hypertension Reports 2001;3:473-80.
54. Bourgault C, Senecal M, Brisson M, Marentette MA, Gregoire JP. Persistence and discontinuation patterns of antihypertensive therapy among newly treated patients: a population-based study. Journal of Human Hypertension 2005;19:607-13.
55. Bloom BS. Continuation of initial antihypertensive medication after 1 year of therapy. Clinical Therapeutics 1998;20:671-81.
56. Hasford J, Mimran A, Simons WR. A population-based European cohort study of persistence in newly diagnosed hypertensive patients. Journal of Human Hypertension 2002;16:569-75.