不同定義日劑量的statins類降血脂藥品於高血壓患者之臨床療效與安全性評估

The evaluation of effectiveness and safety in statins with different defined daily doses for hypertensive patient

黃筱萍(Hsiao-Ping Huang)

指導教授 ： 吳信昇

高雄醫學大學/藥學院/藥學研究所碩士在職專班/碩士(2010年)

摘要

研究目的：
Statins類降血脂藥在目前健保給付下，其達成治療目標所需劑量與達到治療目標後其合適的維持劑量為何，目前仍是眾說紛紜，因此本研究以高血壓病人為研究對象，將其statins類用藥之每日處方劑量（Prescribed Daily Dose，PDD）藉由定義日劑量（Defined Daily Dose，DDD）分為兩組，探討不同種類、不同DDD的statins類用藥在高血壓病人初級預防的臨床療效，並觀察治療對於肝腎功能的影響，與藉由觀察治療期間加入觀察藥品的情形，探討statins的安全性，希望藉此觀察性研究結果作為臨床statins治療的參考依據。

研究方法：
本研究採回溯性研究設計，以2007年1月1日起至2007年12月31日期間於南區某區域教學醫院門診首次開立statins類藥品之高血壓病人為研究對象。依據每日處方劑量分為兩組，當每日處方劑量大於或等於定義日劑量者，定義為高劑量組（atorvastatin ≧ 20 mg、rosuvastatin ≧ 10 mg、fluvastatin ≧ 60 mg pravastatin ≧ 30 mg），每日使用劑量小於定義日劑量者，定義為低劑量組（atorvastatin ＜ 20 mg、rosuvastatin＜10 mg、fluvastatin＜60 mg、pravastatin＜30 mg）。比較高、低劑量的statins治療對於血脂變化幅度、目標血脂達成率與肝腎功能指標的影響。GPT(glutamic pyruvic transaminase)為肝功能指標，serum creatinine為腎功能指標。目標血脂定義包括TC ＜200 mg/dL、LDL-C ＜130 mg/dL、TG < 200 mg/dL + HDL-C > 40 mg/dL、TG < 200 mg/dL + TC/HDL-C < 5。並藉由觀察治療期間加入肝功能改善劑、肌肉鬆弛劑與止痛劑、benzodiazepine（BZD）或non-BZD類安眠藥的情形，探討statins的安全性。

研究結果與討論：
以符合研究定義的221人，共513筆資料進行分析。整體上在介入statins治療後，平均TC降幅為12%，平均LDL-C降幅為15%，約有70-80%的病人可達到治療目標。分析高、低劑量對於血脂的影響上，可發現到當基礎值TC ≦ 200 mg/dL或LDL-C ≦ 120 mg/dL時，使用低劑量，當基礎值TC ≧ 240 mg/dL或LDL-C ≧ 145 mg/dL時，使用高劑量，結果有70-80%的病人可達到治療目標。在低劑量下，atorvastatin對於TC、LDL-C降幅皆優於rosuvastatin，但兩藥品在目標達成率相當，約為70-80%。在高劑量下，atorvastatin與
rosuvastatin在血脂降幅與目標達成率皆相當，目標達成率約為
70-80%。
安全性評估上，整體上介入statins治療後，serum creatinine
（前 1.197±0.306 mg/dL，後 1.174 ± 0.318 mg/dL，P=0.029）呈現明顯改善的趨勢，GPT在治療前、後（前 33.1 ± 23.2 IU/L，後 33.2 ± 21.3 IU/L，P=0.511）則無顯著的變化。Atorvastatin在低劑量下雖呈現serum creatinine改善，但在高劑量下，則呈現serum creatinin增加的情形（3.21 ± 20.04% vs -2.64 ± 6.70%，P=0.063），因此建議atorvastatin在高劑量治療下也應注意追蹤腎功能指標。而atorvastatin（49.10 ± 235.80% vs 6.47 ± 45.22%，P=0.250）與rosuvastatin（10.02 ± 58.05% vs 4.35 ± 29.52%，P=0.487），在高劑量下GPT變化幅度呈現增加的情形，因此在高劑量治療時應謹慎定期追蹤肝功能指標。整體發現22個案(4.3%)在接受治療平均69.6 ± 45.7天後加入BZD或non-BZD類安眠藥治療，且在併服BZD或non-BZD類安眠藥的21位個案（atorvastatin組：15位個案；rosuvastatin組：6位個案）中，其中48%在2個月內發生，90%在4個月內發生。

結論：
高血壓病人當其基礎值TC ≧ 240 mg/dL或LDL-C ≧ 145
mg/dL時，使用高劑量（atorvastatin ≧ 20 mg、rosuvastatin ≧ 10 mg、fluvastatin ≧ 60 mg、pravastatin ≧ 30 mg），當其基礎TC≦200 mg/dL或LDL-C ≦ 120 mg/dL時，使用低劑量（atorvastatin ＜ 20 mg、rosuvastatin ＜ 10 mg、fluvastatin ＜ 60 mg、pravastatin ＜ 30 mg），結果有70-80%的病人可達到治療目標，且低劑量組亦可作為達到治療目標後維持劑量之參考，以符合目前健保給付建議達到治療目標時應考慮減量至最低有效劑量的規定。但在治療過程（尤其是高劑量）應謹慎定期追蹤GPT、serum creatinine，以避免肝、腎方面不良反應發生，且病人接受治療初期（尤其是4個月內）不論高低劑量治療，皆應詢問病人睡眠的情形，以避免精神方面可能的不良反應。

關鍵字

定義日劑量比值 ； statins ； 血脂異常的高血壓病人

並列摘要

Objectives
Statins in the current national health insurance (NHI) payment rules, how many doses can achieve treatment goals and what are optional maintenance doses, they have different opinions. Therefore, this study is focus on hypertensive patients. According to the group, prescribed daily dose (PDD) in accordance with defined daily dose (DDD) was divided into two groups. Investigates different defined daily doses of statins in the hypertensive patients primary prevention clinical effectiveness. Observed during the treatment influence of liver and renal function, and the cases of adding other medication therapy, discussing the safety of statins. Hope the results could help the clinical treatment’s application.

Methods
Electronic medical and pharmacy administrative claims from a regional teaching hospital in south Taiwan and used in this retrospective study. Hypertensive patients use initially on statins between January 1st, 2007 to December 31st, 2007. Divide two groups according to PDD. High dose group in PDD is more than or equal to DDD (atorvastatin ≧20 mg, rosuvastatin ≧10 mg, fluvastatin ≧60 mg, pravastatin ≧30 mg). Low dose group in PDD is less than DDD (atorvastatin ＜20 mg, rosuvastatin ＜10 mg, fluvastatin ＜60 mg, pravastatin ＜30 mg). The objectives were to compare attainment rates of treatment goals an
changes in lipid, serum creatinine, glutamic pyruvic (GPT) levels with high dose group versus low dose group. Definition of the treatment goal: TC ＜200 mg/dL, LDL-C ＜130 mg/dL, TG <200 mg/dL + HDL-C >40 mg/dL, TG <200 mg /dL + TC/HDL-C <5. Other medication includes liver function improvement agents, muscle relaxation and analgesics agents, benzodiazepine (BZD) or non-BZD hypnotics.

Results and Discussions
Analyze with 513 data (data from 221 patients). After statins treatment, its average TC reduction was 12%, average LDL-C reduction was 15%. Analysis of high and low dose effects, when the baseline TC ≦ 200 mg/dL or LDL-C ≦ 120 mg/dL, we can use low dose. And when the baseline TC ≧ 240 mg/dL or LDL-C ≧ 145 mg/dL, we can use high dose. It estimated 70-80% patients that may achieve the treatment goal.
In the low dose group, atorvastatin in TC and LDL-C reduction percentage was superior to rosuvastatin, but two medicines were treating quite about 70-80% of achievement rate of goal. In the high dose group, there was no different in lipid change and achievement rate.
On the safety assess. After statins treatment, the serum creatinine (Before 1.197 ± 0.306 mg/dL, after 1.174 ± 0.318 mg/dL, P=0.029) improved obviously, GPT level change was no different from before and after (Before 33.1 ± 23.2 IU/L, after 33.2 ± 21.3 IU/L, P=0.511).Although serum creatinine shows improvement in the low dose group of the
atorvastatin, serum creatinine shows increases in the high dose group of the atorvastatin (3.21 ± 20.04 % vs -2.64 ± 6.70 %, P=0.063). Therefore, when the treatment uses high dose group of the atorvastatin, it has to follow the renal function. The GPT increases in the high dose of the
atorvastatin (49.10 ± 235.80 % vs 6.47 ± 45.22 %, P=0.250) and rosuvastatin (10.02 ± 58.05 % vs 4.35 ± 29.52 %, P=0.487), and when the treatment uses high dose group, it has to follow the liver function. This result found 22 cases (4.3 %) are being accepted the treatment 69.6 ± 45.7
on average joined the BZD or non-BZD hypnotics treatment after day. Analyze with 21 cases (atorvastatin with 15 cases and rosuvastatin with 6 cases). 48% occurs in 2 months and 90% occurs in 4 months. In atorvastatin and rosuvastatin, takes the BZD or non-BZD hypnotics of
time mostly to appear in the treatment initial period 4 months.

Conclusions
When the baseline TC ≧ 240 mg/dL or LDL-C ≧ 145 mg/dL, we can use high dose (atorvastatin ≧ 20 mg, rosuvastatin ≧ 10 mg,fluvastatin ≧ 60mg, pravastatin ≧ 30 mg). And when the baseline TC ≦ 200 mg/dL or LDL-C ≦ 120 mg/dL, we can use low dose (atorvastatin
＜20 mg, rosuvastatin ＜10 mg, fluvastatin ＜60 mg, pravastatin ＜30 mg). It estimated 70-80% patients that may achieve the treatment goal. We suggest that low dose group can be used as reference for NHI maintenance doses. But the treatment in high dose group, we suggest follow the GPT levels, the serum creatinine levels trace regularly in the
course of treatment. Avoid liver and renal adverse reaction. On the treatment of early stage (especially in the treatment initial period 4 months), in both high and low dose treatment group, pharmacist should inquire the patients sleeping situation. Avoid psychiatric adverse
reactions.

並列關鍵字

defined daily dose ratio ； statins ； hypertensive patient with dyslipidemia

參考文獻

1.Neaton JD, Wentworth D. Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease. Overall findings and differences by age for 316,099 white men. Multiple Risk Factor Intervention Trial Research Group. Arch Intern Med 1992; 152:56–64.

2.NHLBI's Healthy People 2010 Gateway [homepage on the Internet]. Bethesda：U.S. Department of Health and Human Services/National Institutes of Health. Risk Assessment Tool for Estimating 10-year Risk of Developing Hard CHD. Available from：http://hp2010.nhlbihin.net/atpIII/calculator.asp?usertype=prof

3.行政院衛生署：97年度死因統計[database on the Internet] Taiwan :Department of Heath , Executive Yuan , R.O.C [updated 2009-10-01; cited 2009-10-6]. Available from：http://www.doh.gov.tw/CHT2006/DM/DM2_2.aspx?now_fod_list_no=10642&class_no=440&level_no=3

4.James Shepherd., Stuart M. Cobbe, Ian Ford, Christopher G. Isles., A. Ross Lorimer., Peter W. Macfarlane., James H. McKillop, Christopher J. Packard., for The West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333:1301-7.

5.Ian Ford, Heather Murray., Chris J. Packard, James Shepherd, Peter W. Macfarlane., Stuart M. Cobbe, for the West of Scotland Coronary Prevention Study Group.Long-Term Follow-up of the West of Scotland Coronary Prevention Study. N Engl J Med 2007; 357:1477-86.