初始高强度和增量至高强度阿托伐他汀治疗的疗效及相关不良反应研究

发布时间：2018-01-07 12:19

本文关键词：初始高强度和增量至高强度阿托伐他汀治疗的疗效及相关不良反应研究　出处：《河北医科大学》2017年硕士论文　论文类型：学位论文

【摘要】：目的:研究高强度阿托伐他汀(Atorvastatin)治疗动脉粥样硬化性心血管疾病(atheroscl-erotic cardiovascular disease,ASCVD)的疗效及不良反应。方法:1连续入选2015年9月1日至2016年12月30日在河北省邯郸市第一医院心血管内科住院治疗并且接受高强度阿托伐他汀治疗的患者,进行前瞻性队列研究。最终被纳入的研究对象共计525例(男351名,女174名,30~75岁)。2入选标准符合下列高强度阿托伐他汀治疗适应症:(1)年龄≤75岁,存在ASCVD的患者包括:稳定性心绞痛;急性冠脉综合征;心肌梗死病史;冠状动脉搭桥术后或冠状动脉支架植入术后。(2)原发性低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL-C)升高≥4.90mmol/L(190mg/dl)。(3)年龄40-75岁,无ASCVD的糖尿病患者,LDL-C升高1.80-4.89mmol/L(70-189mg/dl)。(4)年龄40-75岁,无ASCVD或糖尿病的患者,LDL-C水平为1.80-4.89mmol/L(70-189mg/dl),并且未来10年ASCVD的发病风险≥7.5%。3排除标准(1)年龄≤18岁或年龄75岁。(2)已经存在严重的肝脏疾病,血清丙氨酸氨基转移酶(alanine aminotransferase,ALT)达到正常上限3倍以上;(3)已经存在严重的肌肉症状或者血清肌酸磷酸激酶(creative phospho kinase,CPK)达到正常上限5倍以上;(4)有严重心力衰竭或心律失常,重度肾功能不全[肾小球滤过率(estimated Glomerular Filtration Rate,eGFR)重度降低者(30 ml/(min·1.73 m2)],自身免疫性疾病,恶性疾病,怀孕或哺乳期;(5)意识、精神、智能障碍,失语及查体不合作的患者。4剔除标准随访期间发生以下情况者:没有坚持规律口服阿托伐他汀治疗;在后续的复诊中血清检测资料或随访数据缺失者。5终点事件的评定标准出现阿托伐他汀相关的肌肉症状并且伴有血清cpk达到正常上限5倍以上;血清alt达到正常上限3倍以上。6记录患者在高强度阿托伐他汀治疗用药前基线指标(包括人口学特征、心血管疾病相关病史及治疗史,吸烟和饮酒状态,主要相关生化指标),在用药后2周、1月及3月安排随访,调查阿托伐他汀相关不良反应,检测主要相关生化指标。评估高强度阿托伐他汀治疗对ascvd患者的治疗疗效及其对于肌肉和肝脏功能等的影响。冠状动脉血管造影和冠状动脉介入治疗没有作为必要的纳入标准。依据相关指南建议,本研究确定的高强度阿托伐他汀治疗剂量是每日40毫克。经专业培训的高年资心血管内科医师监督用药过程,评估治疗疗效和相关不良反应。7空腹血糖(fastingplasmaglucose,fpg)、总胆固醇(totalcholesterol,tc)、甘油三酯(triglyceride,tg)、高密度脂蛋白胆固醇(high-densitylipoproteincholesterol,hdl-c)和ldl-c均采用日立7150全自动生化分析仪测定。ldl-c水平的目标被定义为小于1.8mmol/l或比基线水平降低大于50%。8这项研究得到了河北省邯郸市第一医院伦理委员会的批准,所有患者都签署了知情同意。结果:1根据患者于入院前既往他汀类药物的使用情况分为2组:170例患者入院前已经接受过常规剂量他汀类药物治疗,入院后增加剂量给予高强度阿托伐他汀治疗,作为增加剂量治疗组,占全部研究对象的32.40%;而在入院前从未使用他汀类药物治疗的,入院后直接给予高强度阿托伐他汀治疗的355例患者列入初始治疗组,占全部研究对象的67.60%。研究对象包括稳定性心绞痛患者170例、急性冠脉综合征患者30例及心肌梗死病史患者168例,高血压321例、糖尿病122例,分别占全部研究对象的32.40%、5.70%、32.00%、61.70%和23.6%。有229例患者(43.60%)存在脂肪肝。与剂量增加组比较,在初始治疗组的研究人群中的男性患者比例较高(70.07%vs.58.80%,p0.01),ldl-c水平≥4.90mmol/l的比例较高(21.40%vs.1.20%,p0.01),高血压及使用降压药的比例较低(54.00%vs.77.60%,47.90%vs.74.10%,p0.01)、糖尿病及使用降糖药的比例较低(19.30%vs.32.40%,13.00%vs.28.20%,p0.01)。与剂量增加组比较,在初始治疗组的研究人群中的空腹血糖水平较低(8.44±2.81vs.9.06±3.26,p=0.03),总胆固醇水平较高(5.70±2.00vs.5.32±1.44,p=0.03),ldl-c水平较高(3.23±1.49vs.2.58±0.91,p0.01),血清cpk水平较高(72.34±19.59vs.67.08±20.79,p0.01)。两组间比较,冠状动脉疾病的类型构成比无明显差异,吸烟、饮酒、非酒精性脂肪肝发病率差异无统计学意义,甘油三酯、高密度脂蛋白胆固醇、alt和超敏c反应蛋白差异无统计学意义。2全部研究对象中ldl-c指标达标118例(低密度脂蛋白胆固醇比基线降低50%或者ldl-c降至1.80mmol/l,达标率22.50%),其中ldl-c比基线降低50%的82例(达标率15.60%),ldl-c降至1.80mmol/l的76例(达标率14.50%)。与剂量增加组比较,在初始治疗组的研究人群中的ldl-c达标率更高(25.10%vs.17.10%,p=0.04),但是ldl-c水平达到1.80mmol/l(70mg/dl)或者ldl-c水平降低50%的单一指标差异无统计学意义。初始治疗组和剂量增加组患者的ldl-c、crp在随访过程中均有所下降[3.23±1.66vs.3.11±1.61,2.99±1.62,2.50±1.341.42(0.50,3.39),1.33(0.49,3.27),1.24(0.47,3.06),1.10(0.38,2.91)2.58±0.91vs.2.50±0.86,2.51±0.90,2.27±0.871.38(0.48,3.40),1.30(0.41,3.17),1.27(0.39,3.04),1.23(0.33,2.95)。p值均0.01]。3全部研究人群共计报告他汀类药物肌肉症状(statinassociatedmusclesymptoms,sams)37例(发病率7.00%),其中肌肉疼痛19例(发病率3.60%)、肌肉僵硬21例(发病率4.00%)、肌肉无力5例(发病率1.00%);cpk升高≥正常上限5倍患者18例(发病率3.40%);alt升高≥正常上限3倍患者9例(发病率1.70%);符合终点事件诊断标准而停用阿托伐他汀的24例(发病率4.60%),其中2例(发病率0.38%)同时出现肌肉症状、cpk升高≥正常上限5倍以及alt升高≥正常上限3倍的情况。大多数(55.20%)的阿托伐他汀相关不良反应出现在阿托伐他汀开始治疗或者剂量增加后的1个月内。501例(95.40%)患者在最后一次随访后,仍在继续高强度阿托伐他汀治疗。与剂量增加组比较,在初始治疗组的研究人群中报告的阿托伐他汀相关的肌肉症状患者比例较高(8.70%vs.3.50%,P=0.03)及总的终点事件比例较高(5.60%vs.2.40%,P=0.04)。阿托伐他汀相关的单一不良反应如肌肉疼痛、肌肉僵硬、肌肉无力、CPK升高≥正常上限5倍、消化道症状、ALT升高≥正常上限3倍检出率组间比较差异无统计学意义。4全部研究人群的ALT水平在随访2周及1月时较基线水平升高[28.50(23.37,35.40)vs.31.10(24.55,41.85),28.72(22.50,40.73)。P值均0.01],随访3月时检测结果与基线水平比较差异无统计学意义;CPK水平于随访1月及3月时较基线水平升高[68.00(56.00,82.00)vs.72.86(47.47,99.75),69.33(53.49,90.35)。P值均0.01]。在分组观察,初始治疗组人群的ALT水平在随访2周及1月、3月时较基线水平均升高[28.80(23.4,35.40)vs.32.30(24.90,45.00),30.83(22.23,40.65),29.20(21.27,35.55)。P值均0.01];CPK水平于随访1月及3月时较基线水平升高[69.00(58.00,84.00)),78.38(56.72,103.08),72.28(56.22,92.52),P值均0.01]。剂量增加组人群的ALT水平在随访2周、1月时较基线水平均升高[28.00(23.19,35.30)vs.30.55(23.40,40.01),31.12(22.79,40.96)。P值均0.01),但是在随访3月时与基线水平比较差异无统计学意义;CPK水平在随访2周及1月、3月时与基线水平比较差异均无统计学意义。结论:高强度阿托伐他汀治疗后研究对象的LDL-C、CRP水平下降,初始治疗组的LDL-C水平达标率高于剂量增加组。初始治疗组的相关肌肉症状及终点事件比例高于剂量增加组。
[Abstract]:Objective: To study the high strength of atorvastatin (Atorvastatin) treatment of atherosclerotic cardiovascular disease (atheroscl-erotic cardiovascular, disease, ASCVD) the efficacy and adverse reaction. Methods: 1 consecutive patients from September 1, 2015 to December 30, 2016 in the first hospital of Hebei city of Handan province cardiovascular hospitalization and receiving intensive atorvastatin treatment in patients with prospective cohort study the object of study. Eventually included in a total of 525 cases (male 351, female 174, age 30~75).2 criteria in accordance with the following high intensity atorvastatin therapy indications: (1) aged less than 75 years, including the presence of ASCVD patients: stable angina; acute coronary syndrome; myocardial infarction; after coronary artery bypass surgery or coronary artery stent implantation. (2) primary low density lipoprotein cholesterol (low-density lipoprotein, cholesterol, LDL-C). More than 4.90mmol/L (190mg/dl). (3) 40-75 years of age, diabetic patients without ASCVD, LDL-C increased 1.80-4.89mmol/L (70-189mg/dl). (4) aged 40-75 years old, no ASCVD or diabetes, the level of LDL-C 1.80-4.89mmol/L (70-189mg/dl), and the next 10 years, the risk of ASCVD 7.5%.3 or exclusion criteria (1) age less than 18 years or 75 years of age. (2) severe liver disease already exists, serum alanine aminotransferase (alanine, aminotransferase, ALT) reached more than 3 times the upper limit of normal; (3) severe muscle symptoms or serum creatine phosphokinase (Creative phospho kinase, has CPK) reached more than 5 times the upper limit of normal (4;) have serious heart failure or arrhythmia, severe renal insufficiency (glomerular filtration rate estimated Glomerular [Filtration Rate, eGFR (30) severe decrease of ml/ (min - 1.73 m2)], autoimmune diseases, malignant diseases, pregnancy or lactation Milk period; (5) consciousness, spirit, mental retardation, aphasia and the following occurs check uncooperative patients.4 exclusion criteria during follow-up: no regular oral atorvastatin treatment; in the follow-up visit in serum detection data or follow-up data deletion.5 standard end point events appear atorvastatin the muscle symptoms and associated with serum CPK reached more than 5 times the upper limit of normal; the serum ALT reached more than 3 times the upper limit of normal.6 records of patients of atorvastatin treatment in high intensity atorvastatin baseline characters (including demographic characteristics, history of cardiovascular disease and treatment history, smoking and drinking status, the main biochemical indexes), after treatment 2 weeks in January and March, arrange follow-up survey, atorvastatin related adverse effects of statins, mainly related biochemical indexes. The evaluation of high strength of atorvastatin in the treatment of ASCVD patients and its treatment Effect on muscle and liver function. Coronary angiography and coronary intervention is not necessary as inclusion criteria. According to the relevant guidelines, this study determined the effect of high intensity of atorvastatin dose is 40 mg daily. Senior cardiovascular physician medication supervision by professional training, evaluation of therapeutic effect and related the adverse reaction of.7 fasting blood glucose (fastingplasmaglucose, FPG), total cholesterol (Totalcholesterol, TC), triglycerides (triglyceride, TG), high density lipoprotein cholesterol (high-densitylipoproteincholesterol, HDL-C) and LDL-C were using Hitachi 7150 automatic biochemical analyzer.Ldl-c level target is defined as less than 1.8mmol/l or lower than 50%.8 this baseline study was conducted in the first hospital of Hebei City of Handan province by the ethics committee, all patients signed informed Agree. Results: 1 patients in the hospital according to the use of prior statin drugs were divided into 2 groups: 170 patients before admission had received conventional dose statin therapy after admission increased doses of atorvastatin in the treatment of high strength, as the increasing dose treatment group, the total research object in 32.40%; never before admission statin treatment, 355 cases after admission to high strength with atorvastatin in initial treatment group, accounting for all subjects of the 67.60%. study included 170 patients with stable angina pectoris, 168 cases of acute coronary syndrome patients and 30 cases of myocardial infarction patients, 321 cases of hypertension. 122 cases of diabetes, accounted for 32.40% of the study participants, 5.70%, 32%, 61.70% and 23.6%. of 229 patients (43.60%) had fatty liver. Compared with the dose increased, the initial research in the treatment group The proportion of male patients was higher (70.07%vs.58.80%, P0.01), LDL-C level greater than or equal to a higher proportion of 4.90mmol/l (21.40%vs.1.20%, P0.01), the proportion of hypertension and use of antihypertensive medications was low (54.00%vs.77.60%, 47.90%vs.74.10%, P0.01), diabetes mellitus and the proportion of use of hypoglycemic drugs is low (19.30%vs.32.40%, 13.00%vs.28.20%, P0.01). Compared with the dose in the study population increased, the initial treatment group in the fasting blood glucose level is low (8.44 + 2.81vs.9.06 + 3.26, p=0.03), total cholesterol level (5.70 + 2.00vs.5.32 + 1.44, p= 0.03), higher levels of LDL-C (3.23 + 1.49vs.2.58 + 0.91, P0.01), high level of serum CPK (72.34 + 19.59vs.67.08 + 20.79, P0.01). The comparison between the two groups, the type of coronary artery disease constituent ratio had no significant difference in smoking, drinking alcohol, non-alcoholic fatty liver disease rate difference was statistically significant, triglyceride, high density lipoprotein cholesterol, a No significant LT and high sensitive C reactive protein between.2 LDL-C index in all the research object of compliance in 118 cases (low density lipoprotein cholesterol than baseline decreased by 50% or LDL-C to 1.80mmol/l, the standard rate of 22.50%), including 82 cases of LDL-C (50% lower than the baseline compliance rate of 15.60%), 76 cases (LDL-C to 1.80mmol/l standard the rate of 14.50%). Compared with the dose increased, the initial treatment group in the study population in the success rate of LDL-C higher (25.10%vs.17.10%, p=0.04), but the level of LDL-C reached 1.80mmol/l (70mg/dl) or lower the level of LDL-C 50% of the single index showed no significant difference. The initial treatment group and dose group were LDL-C, CRP decreased [3.23 + 1.66vs.3.11 + 1.61,2.99 + 1.62,2.50 + 1.341.42 during follow-up (0.50,3.39), 1.33 (0.49,3.27), 1.24 (0.47,3.06), 1.10 (0.38,2.91) 2.58 + 0.91vs.2.50 + 0.86,2.51 + 0.90,2.27 + 0.871.38 (0. 48,3.40), 1.30 (0.41,3.17), 1.27 (0.39,3.04), 1.23 (0.33,2.95) 0.01].3 value of all the study population were reported statin muscle symptoms of.P (statinassociatedmusclesymptoms, SAMs) in 37 cases (incidence rate 7%), including 19 cases of muscle pain (incidence rate 3.60%), 21 cases of muscle stiffness (incidence rate 4%) muscle weakness, 5 cases (incidence rate 1%); CPK increased more than 5 times the upper limit of normal, 18 cases of patients (incidence rate 3.40%); ALT increased more than 3 times the upper limit of normal, 9 cases of patients (incidence rate 1.70%); end point events with diagnostic criteria and discontinuation of atorvastatin in 24 cases (incidence rate 4.60%), 2 cases (incidence rate 0.38%) and muscle symptoms, Cpk increased more than 5 times the upper limit of normal and ALT increased more than 3 times the upper limit of normal situation. The majority (55.20%) of atorvastatin statin related adverse reactions occurred in atorvastatin began 1 months after the treatment or dose increase of.501 cases (95.40% patients) At last follow-up, continued high strength. Atorvastatin treatment group compared with the dose increased, the initial report in the study group treatment group in the proportion of atorvastatin statin related muscle symptoms were higher (8.70%vs.3.50%, P=0.03) and a higher proportion of the total end point events (5.60%vs.2.40%, P=0.04) atorvastatin. A single statin related adverse reactions such as muscle pain, muscle stiffness, muscle weakness, CPK increased more than 5 times the upper limit of normal, gastrointestinal symptoms, ALT increased more than 3 times the upper limit of normal detection rate was no statistically significant difference between the.4 level of ALT in all subjects were followed for 2 weeks and in January when compared to the baseline level ([28.50 23.37,35.40) vs.31.10 (24.55,41.85), 28.72 (22.50,40.73).P value was 0.01], followed in March compared the test results with the baseline level of the difference was not statistically significant; CPK level in January and March were compared with baseline levels [ 68 (56.00,82.00) vs.72.86 (47.47,99.75), 69.33 (53.49,90.35).P value was 0.01]. in the observation group, initial treatment groups were followed for 2 weeks and ALT level in January March, when compared to the baseline levels were elevated [28.80 (23.4,35.40) vs.32.30 (24.90,45.00), 30.83 (22.23,40.65), 29.20 (21.27,35.55).P value was 0.01] the level of CPK in January; follow-up and March when compared to the baseline level [69.00 (58.00,84.00)), 78.38 (56.72103.08), 72.28 (56.22,92.52), P ALT levels were 0.01]. dose groups at 2 weeks of follow-up, in January when compared to the baseline levels were elevated [28.00 (23.19,35.30) vs.30.55 (23.40,40.01), 31.12 (22.79,40.96).P 0.01), but in March at baseline and follow-up showed no significant difference; the level of CPK in the follow-up of 2 weeks in January and March, when compared with baseline differences were not statistically significant. Conclusion: the research object of high strength after atorvastatin therapy The level of LDL-C and CRP decreased. The LDL-C level of the initial treatment group was higher than that of the dose increasing group. The proportion of the related muscle symptoms and terminal events in the initial treatment group was higher than that in the dose increasing group.

【学位授予单位】：河北医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R54

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