不同剂量阿托伐他汀治疗对缺血性卒中/TIA患者伴颅内动脉粥样硬化性狭窄的影响
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摘要
目的：本研究一方面观察不同剂量阿托伐他汀对血低密度脂蛋白胆固醇(low-density lipoprotein cholesterol, LDL-C)、踝臂指数(ankle-brachial index, ABI)及颈动脉内-中膜厚度(carotid intima-media thickness, CIMT)的影响和对颅内动脉粥样硬化(atherosclerosis, AS)的抑制或逆转作用；另一方面观察不同剂量阿托伐他汀治疗的安全性及对脑血管不良事件复发率的影响,进而评估不同剂量阿托伐他汀治疗对伴有颅内动脉粥样硬化性狭窄的缺血性卒中(ischemic stroke)／短暂性脑缺血发作(transient ischemic attack, TIA)患者的二级预防作用。
方法：2008年9月-2010年4月收集大连医科大学附属第一医院诊断为缺血性卒中／TIA且伴颅内动脉粥样硬化性狭窄的患者150例,随机分成A、B、C三组,每组50例。A组为强化治疗组(口服阿托伐他汀20mg／d)；B组为标准治疗组(口服阿托伐他汀10mg／d)；C组为对照组(未口服阿托伐他汀)。三组患者均规范应用降血压、降血糖及抗血小板聚集等药物,且未应用其他类型降血脂药物。治疗随访9个月。观察治疗前后低密度脂蛋白(LDL-C)、踝臂指数(ABI)、颈动脉内-中膜厚度(CIMT)、颅内动脉狭窄度的变化,并统计不同剂量阿托伐他汀治疗所发生的不良反应及脑血管不良事件的复发率。
结果：
1.A组、B组患者治疗1、3、6、9个月后复诊时LDL-C水平较初诊时均有所下降(P<0.05)。A组患者分别治疗1、3、6、9个月后复诊时各时间点的LDL-C水平比较均未见明显变化(P>0.05); B组患者分别治疗1、3、6、9个月后复诊时各时间点的LDL-C水平比较均未见明显变化(P>0.05)。C组患者9个月后复诊时LDL-C水平与初诊时比较无明显变化(P>0.05)。治疗1、3、6、9个月后复诊时A组和B组患者较C组患者的LDL-C水平均有所下降(P<0.05),且A组较B组患者下降更明显(P<0.05)。
2.A组患者治疗9个月后复诊与初诊时ABI比较有所提高(P<0.05)。B组、C组患者治疗9个月后复诊与初诊时ABI比较无明显变化(P>0.05)。治疗9个月后复诊时,A组患者较B组及C组患者的ABI有所提高(P<0.05),B组和C组患者的ABI比较无明显差异(P>0.05)。
3.A组患者治疗9个月后复诊与初诊时CIMT比较有所降低(P<0.05)。B组、C组患者治疗9个月后复诊与初诊时CIMT比较无明显变化(P>0.05)。治疗9个月后复诊时,A组患者较B组及C组患者的CIMT有所降低(P<0.05),B组和C组患者的CIMT比较无明显差异(P>0.05)。
4.A组、B组、C组患者治疗9个月后复诊与初诊时颅内动脉狭窄度比较均无明显变化(P>0.05)。治疗9个月后复诊时,将A、B、C三组患者的颅内动脉狭窄度进行组间比较,均无明显差异(P>0.05)。
5.A组患者9个月内的脑血管不良事件复发率明显低于B组及C组(P<0.05),B组与C组患者9个月内的脑血管不良事件复发率比较无明显差异(P>0.05)。A、B、C三组均未见严重不良反应。
结论：
1.阿托伐他汀10mg／d及20mg／d连续应用1个月即可以降低LDL-C水平，且20mg／d作用优于10mg／d；阿托伐他汀连续应用1、3、6、9个月后LDL-C维持于相对稳定的水平。
2.阿托伐他汀20mg／d连续应用9个月可以提高踝臂指数。
3.阿托伐他汀20mg／d连续应用9个月可以降低颈动脉内-中膜厚度。
4.阿托伐他汀20mg／d及10mg／d连续应用9个月未明显改善颅内动脉粥样硬化性狭窄。
5.阿托伐他汀20mg／d可以降低脑血管事件的复发率。
Objective:This study observes the effect of different doses of atorvastatin on low-density lipoprotein cholesterol (LDL-C), ankle-brachial index (ABI), carotid intima-media thickness (IMT) and intracranial atherosclerosis. It also observes the security as well as the incidence of cerebrovascular events of different doses of atorvastatin in order to assess the secondary prevention effect of different doses of atorvastatin on patients with ischemic stroke/TIA and intracranial atherosclerotic stenosis.
Methods:Total 150 patients with ischemic stroke/transient ischemic attack (TIA) and atherosclerotic stenosis were enrolled from September, 2008 to April,2010 in the First Affiliated Hospital of Dalian Medical University. All of the patients were divided into three groups randomly-group A, group B and group C, and each included 50 patients. Group A was named intensive therapy group which was given atorvastatin of 20mg every day for 9 months. Group B was named standard therapy group which was given atorvastatin of 10mg every day for 9 months. Group C was named control group which was not given atorvastatin. All patients took medicine to control blood pressure, blood sugar and against the process of platelet aggregation. No other types of cholesterol-lowering drugs were used. All patients accepted treatment and follow-up for 9 months. Observe the changes of low-density lipoprotein cholesterol (LDL-C), ankle-brachial index (ABI), carotid intima-media thickness (IMT) and intracranial artery stenosis before and after the treatment, and also observe the side effects as well as the incidence of cerebrovascular events of different doses of atorvastatin.
Results:
(1) Comparing to the beginning, the level of LDL-C reduced in group A and group B after treatment for 1,3,6 and 9 months (P<0.05). The level of LDL-C did not change obviously in group A at each period after treatment for 1,3,6 and 9 months (P>0.05). The level of LDL-C did not change obviously in group B at each period after treatment for 1,3,6, and 9 months (P>0.05). Comparing to the beginning, the level of LDL-C did not change obviously in group C after 1,3,6 and 9 months (P>0.05). Comparing to group C, the level of LDL-C in group A and group B reduced after treatment for 1,3,6 and 9 months(P<0.05), and the changes in group A were more obvious than in group B(P<0.05).
(2) Comparing to the beginning, ABI increased in group A after treatment for 9 months (P<0.05). Comparing to the beginning, ABI did not change obviously in group B and group C after 9 months (P>0.05). Comparing to group B and group C, ABI in group A increased after treatment for 9 months(P<0.05). ABI in group B and group C were not obviously different after 9 months(P>0.05).
(3) Comparing to the beginning, CIMT decreased in group A after treatment for 9 months (P<0.05). Comparing to the beginning, CIMT did not change obviously in group B and group C after 9 months (P>0.05). Comparing to group B and group C, CIMT in group A decreased after treatment for 9 months(P<0.05). CIMT in group B and group C were not obviously different after 9 months(P>0.05).
(4) Comparing to the beginning, intracranial artery stenosis did not change obviously in group A, group B and group C after 9 months (P>0.05). Intracranial artery stenosis in group A, group B and group C were not obviously different after 9 months(P>0.05).
(5) Comparing to group B and group C, the incidence of cerebrovascular events in group A was lower in the nine months (P>0.05). The incidence of cerebrovascular events in group B and group C were not obviously different in the nine months (P>0.05). No serious side effects were discovered in the three groups.
Conclusions:
(1) Treatment of atorvastatin with 10mg/d and 20mg/d for 1 month can reduce the level of LDL-C, and the effect of 20mg/d is more obvious. The level of LDL-C can be maintained steadily after treatment of atorvastatin for 1,3,6 and 9 months.
(2) Treatment of atorvastatin with 20mg/d for 9 months can increase ABI.
(3) Treatment of atorvastatin with 20mg/d for 9 months can reduce CIMT.
(4) Treatment of atorvastatin with 10mg/d and 20mg/d for 9 months cannot improve intracranial artery stenosis obviously.
(5) Treatment of atorvastatin with 20mg/d can reduce The incidence of cerebrovascular events.
方法：2008年9月-2010年4月收集大连医科大学附属第一医院诊断为缺血性卒中／TIA且伴颅内动脉粥样硬化性狭窄的患者150例,随机分成A、B、C三组,每组50例。A组为强化治疗组(口服阿托伐他汀20mg／d)；B组为标准治疗组(口服阿托伐他汀10mg／d)；C组为对照组(未口服阿托伐他汀)。三组患者均规范应用降血压、降血糖及抗血小板聚集等药物,且未应用其他类型降血脂药物。治疗随访9个月。观察治疗前后低密度脂蛋白(LDL-C)、踝臂指数(ABI)、颈动脉内-中膜厚度(CIMT)、颅内动脉狭窄度的变化,并统计不同剂量阿托伐他汀治疗所发生的不良反应及脑血管不良事件的复发率。
结果：
1.A组、B组患者治疗1、3、6、9个月后复诊时LDL-C水平较初诊时均有所下降(P<0.05)。A组患者分别治疗1、3、6、9个月后复诊时各时间点的LDL-C水平比较均未见明显变化(P>0.05); B组患者分别治疗1、3、6、9个月后复诊时各时间点的LDL-C水平比较均未见明显变化(P>0.05)。C组患者9个月后复诊时LDL-C水平与初诊时比较无明显变化(P>0.05)。治疗1、3、6、9个月后复诊时A组和B组患者较C组患者的LDL-C水平均有所下降(P<0.05),且A组较B组患者下降更明显(P<0.05)。
2.A组患者治疗9个月后复诊与初诊时ABI比较有所提高(P<0.05)。B组、C组患者治疗9个月后复诊与初诊时ABI比较无明显变化(P>0.05)。治疗9个月后复诊时,A组患者较B组及C组患者的ABI有所提高(P<0.05),B组和C组患者的ABI比较无明显差异(P>0.05)。
3.A组患者治疗9个月后复诊与初诊时CIMT比较有所降低(P<0.05)。B组、C组患者治疗9个月后复诊与初诊时CIMT比较无明显变化(P>0.05)。治疗9个月后复诊时,A组患者较B组及C组患者的CIMT有所降低(P<0.05),B组和C组患者的CIMT比较无明显差异(P>0.05)。
4.A组、B组、C组患者治疗9个月后复诊与初诊时颅内动脉狭窄度比较均无明显变化(P>0.05)。治疗9个月后复诊时,将A、B、C三组患者的颅内动脉狭窄度进行组间比较,均无明显差异(P>0.05)。
5.A组患者9个月内的脑血管不良事件复发率明显低于B组及C组(P<0.05),B组与C组患者9个月内的脑血管不良事件复发率比较无明显差异(P>0.05)。A、B、C三组均未见严重不良反应。
结论：
1.阿托伐他汀10mg／d及20mg／d连续应用1个月即可以降低LDL-C水平，且20mg／d作用优于10mg／d；阿托伐他汀连续应用1、3、6、9个月后LDL-C维持于相对稳定的水平。
2.阿托伐他汀20mg／d连续应用9个月可以提高踝臂指数。
3.阿托伐他汀20mg／d连续应用9个月可以降低颈动脉内-中膜厚度。
4.阿托伐他汀20mg／d及10mg／d连续应用9个月未明显改善颅内动脉粥样硬化性狭窄。
5.阿托伐他汀20mg／d可以降低脑血管事件的复发率。
Objective:This study observes the effect of different doses of atorvastatin on low-density lipoprotein cholesterol (LDL-C), ankle-brachial index (ABI), carotid intima-media thickness (IMT) and intracranial atherosclerosis. It also observes the security as well as the incidence of cerebrovascular events of different doses of atorvastatin in order to assess the secondary prevention effect of different doses of atorvastatin on patients with ischemic stroke/TIA and intracranial atherosclerotic stenosis.
Methods:Total 150 patients with ischemic stroke/transient ischemic attack (TIA) and atherosclerotic stenosis were enrolled from September, 2008 to April,2010 in the First Affiliated Hospital of Dalian Medical University. All of the patients were divided into three groups randomly-group A, group B and group C, and each included 50 patients. Group A was named intensive therapy group which was given atorvastatin of 20mg every day for 9 months. Group B was named standard therapy group which was given atorvastatin of 10mg every day for 9 months. Group C was named control group which was not given atorvastatin. All patients took medicine to control blood pressure, blood sugar and against the process of platelet aggregation. No other types of cholesterol-lowering drugs were used. All patients accepted treatment and follow-up for 9 months. Observe the changes of low-density lipoprotein cholesterol (LDL-C), ankle-brachial index (ABI), carotid intima-media thickness (IMT) and intracranial artery stenosis before and after the treatment, and also observe the side effects as well as the incidence of cerebrovascular events of different doses of atorvastatin.
Results:
(1) Comparing to the beginning, the level of LDL-C reduced in group A and group B after treatment for 1,3,6 and 9 months (P<0.05). The level of LDL-C did not change obviously in group A at each period after treatment for 1,3,6 and 9 months (P>0.05). The level of LDL-C did not change obviously in group B at each period after treatment for 1,3,6, and 9 months (P>0.05). Comparing to the beginning, the level of LDL-C did not change obviously in group C after 1,3,6 and 9 months (P>0.05). Comparing to group C, the level of LDL-C in group A and group B reduced after treatment for 1,3,6 and 9 months(P<0.05), and the changes in group A were more obvious than in group B(P<0.05).
(2) Comparing to the beginning, ABI increased in group A after treatment for 9 months (P<0.05). Comparing to the beginning, ABI did not change obviously in group B and group C after 9 months (P>0.05). Comparing to group B and group C, ABI in group A increased after treatment for 9 months(P<0.05). ABI in group B and group C were not obviously different after 9 months(P>0.05).
(3) Comparing to the beginning, CIMT decreased in group A after treatment for 9 months (P<0.05). Comparing to the beginning, CIMT did not change obviously in group B and group C after 9 months (P>0.05). Comparing to group B and group C, CIMT in group A decreased after treatment for 9 months(P<0.05). CIMT in group B and group C were not obviously different after 9 months(P>0.05).
(4) Comparing to the beginning, intracranial artery stenosis did not change obviously in group A, group B and group C after 9 months (P>0.05). Intracranial artery stenosis in group A, group B and group C were not obviously different after 9 months(P>0.05).
(5) Comparing to group B and group C, the incidence of cerebrovascular events in group A was lower in the nine months (P>0.05). The incidence of cerebrovascular events in group B and group C were not obviously different in the nine months (P>0.05). No serious side effects were discovered in the three groups.
Conclusions:
(1) Treatment of atorvastatin with 10mg/d and 20mg/d for 1 month can reduce the level of LDL-C, and the effect of 20mg/d is more obvious. The level of LDL-C can be maintained steadily after treatment of atorvastatin for 1,3,6 and 9 months.
(2) Treatment of atorvastatin with 20mg/d for 9 months can increase ABI.
(3) Treatment of atorvastatin with 20mg/d for 9 months can reduce CIMT.
(4) Treatment of atorvastatin with 10mg/d and 20mg/d for 9 months cannot improve intracranial artery stenosis obviously.
(5) Treatment of atorvastatin with 20mg/d can reduce The incidence of cerebrovascular events.
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11. Christie MB, Nambi V. Markers of inflammation and their clinical significance [J]. Atherosclerosis Supp lements,2005,6:21-29
12. Smilde T J, Van Wissen S. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP):a prospec-tive, randomized, double2blind trial [J]. The Lancet 2001,24 (6):357-361
13.Jacobson TA."The lower the Better"in hypercholesterolemia therapy:a reliable clinical guideline [J].Ann Intern Med 2000,133(11):549-554
14.Rosa EM, Kramer C, Castro I. Association between coronary artery arteriosc-lerosis and the intima-media thickness of the common carotid artery measured on ultrasonography.Arq Bras Cardiol,2003,80(6):589-592
15. QL, Mo L, Yang TL, et al. Effect of different doses of atorvastatin on adhesion molecules of the patients undergoing percutaneous coronary intervention [J]. Zhong Nan DaXue Xue Bao Yi Xue Ban,2006,31:914-916
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18.刘志军,范生尧.他汀类药物预防缺血性脑卒中及其机制的研究进展.国外医学脑血管疾病分册,2003,7：261-262
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20. Amin, Hanjani S, Stagliano NE, Yamada M, et al. Mevastatin, an HMG-CoA red-ucetase inhibitor, reduces stroke damage and up regulates endothelial nitric oxide synthase in micelStroke,2001,32:980-986
21.Vaughan CJ, Delanty N. Neuroprotective properties of stains in cerebral ische-mia and stroke. Stroke,1999,30:1969-1973
22. O'Rourke F, Dean N, Akhtar N, et al. Current and future concepts in stroke pre-ventionl CAMJ,2004,170:1123-1331
23. Kirshner HS. Medical prevention of stroke,2003 South Med J,2003,96:354-358
24. Wang E, Casciano CN, Clement RP, et al. HMG-CoA reeducate inhibitors (stains) characterized as direct inhibitors of Polycoprotein. Pharm Res,2001,18:800-806
25.LaufsU, Gertz K, Huang P, et al. Atorvastain up regulates type III nitric oxide synthase in thrombocytes, decreases platelet activation, and protects from cere-bral ischemia in normal cholesterol lemic mice. Stroke,2000,31:2442-2449