發(fā)布時間：2018-01-07 12:19

  本文關鍵詞：初始高強度和增量至高強度阿托伐他汀治療的療效及相關不良反應研究　出處：《河北醫(yī)科大學》2017年碩士論文　論文類型：學位論文

  更多相關文章： 阿托伐他汀 高強度治療 療效 不良事件 動脈粥樣硬化性心血管疾病

【摘要】：目的:研究高強度阿托伐他汀(Atorvastatin)治療動脈粥樣硬化性心血管疾病(atheroscl-erotic cardiovascular disease,ASCVD)的療效及不良反應。方法:1連續(xù)入選2015年9月1日至2016年12月30日在河北省邯鄲市第一醫(yī)院心血管內科住院治療并且接受高強度阿托伐他汀治療的患者,進行前瞻性隊列研究。最終被納入的研究對象共計525例(男351名,女174名,30~75歲)。2入選標準符合下列高強度阿托伐他汀治療適應癥:(1)年齡≤75歲,存在ASCVD的患者包括:穩(wěn)定性心絞痛;急性冠脈綜合征;心肌梗死病史;冠狀動脈搭橋術后或冠狀動脈支架植入術后。(2)原發(fā)性低密度脂蛋白膽固醇(low-density lipoprotein cholesterol,LDL-C)升高≥4.90mmol/L(190mg/dl)。(3)年齡40-75歲,無ASCVD的糖尿病患者,LDL-C升高1.80-4.89mmol/L(70-189mg/dl)。(4)年齡40-75歲,無ASCVD或糖尿病的患者,LDL-C水平為1.80-4.89mmol/L(70-189mg/dl),并且未來10年ASCVD的發(fā)病風險≥7.5%。3排除標準(1)年齡≤18歲或年齡75歲。(2)已經(jīng)存在嚴重的肝臟疾病,血清丙氨酸氨基轉移酶(alanine aminotransferase,ALT)達到正常上限3倍以上;(3)已經(jīng)存在嚴重的肌肉癥狀或者血清肌酸磷酸激酶(creative phospho kinase,CPK)達到正常上限5倍以上;(4)有嚴重心力衰竭或心律失常,重度腎功能不全[腎小球濾過率(estimated Glomerular Filtration Rate,eGFR)重度降低者(30 ml/(min·1.73 m2)],自身免疫性疾病,惡性疾病,懷孕或哺乳期;(5)意識、精神、智能障礙,失語及查體不合作的患者。4剔除標準隨訪期間發(fā)生以下情況者:沒有堅持規(guī)律口服阿托伐他汀治療;在后續(xù)的復診中血清檢測資料或隨訪數(shù)據(jù)缺失者。5終點事件的評定標準出現(xiàn)阿托伐他汀相關的肌肉癥狀并且伴有血清cpk達到正常上限5倍以上;血清alt達到正常上限3倍以上。6記錄患者在高強度阿托伐他汀治療用藥前基線指標(包括人口學特征、心血管疾病相關病史及治療史,吸煙和飲酒狀態(tài),主要相關生化指標),在用藥后2周、1月及3月安排隨訪,調查阿托伐他汀相關不良反應,檢測主要相關生化指標。評估高強度阿托伐他汀治療對ascvd患者的治療療效及其對于肌肉和肝臟功能等的影響。冠狀動脈血管造影和冠狀動脈介入治療沒有作為必要的納入標準。依據(jù)相關指南建議,本研究確定的高強度阿托伐他汀治療劑量是每日40毫克。經(jīng)專業(yè)培訓的高年資心血管內科醫(yī)師監(jiān)督用藥過程,評估治療療效和相關不良反應。7空腹血糖(fastingplasmaglucose,fpg)、總膽固醇(totalcholesterol,tc)、甘油三酯(triglyceride,tg)、高密度脂蛋白膽固醇(high-densitylipoproteincholesterol,hdl-c)和ldl-c均采用日立7150全自動生化分析儀測定。ldl-c水平的目標被定義為小于1.8mmol/l或比基線水平降低大于50%。8這項研究得到了河北省邯鄲市第一醫(yī)院倫理委員會的批準,所有患者都簽署了知情同意。結果:1根據(jù)患者于入院前既往他汀類藥物的使用情況分為2組:170例患者入院前已經(jīng)接受過常規(guī)劑量他汀類藥物治療,入院后增加劑量給予高強度阿托伐他汀治療,作為增加劑量治療組,占全部研究對象的32.40%;而在入院前從未使用他汀類藥物治療的,入院后直接給予高強度阿托伐他汀治療的355例患者列入初始治療組,占全部研究對象的67.60%。研究對象包括穩(wěn)定性心絞痛患者170例、急性冠脈綜合征患者30例及心肌梗死病史患者168例,高血壓321例、糖尿病122例,分別占全部研究對象的32.40%、5.70%、32.00%、61.70%和23.6%。有229例患者(43.60%)存在脂肪肝。與劑量增加組比較,在初始治療組的研究人群中的男性患者比例較高(70.07%vs.58.80%,p0.01),ldl-c水平≥4.90mmol/l的比例較高(21.40%vs.1.20%,p0.01),高血壓及使用降壓藥的比例較低(54.00%vs.77.60%,47.90%vs.74.10%,p0.01)、糖尿病及使用降糖藥的比例較低(19.30%vs.32.40%,13.00%vs.28.20%,p0.01)。與劑量增加組比較,在初始治療組的研究人群中的空腹血糖水平較低(8.44±2.81vs.9.06±3.26,p=0.03),總膽固醇水平較高(5.70±2.00vs.5.32±1.44,p=0.03),ldl-c水平較高(3.23±1.49vs.2.58±0.91,p0.01),血清cpk水平較高(72.34±19.59vs.67.08±20.79,p0.01)。兩組間比較,冠狀動脈疾病的類型構成比無明顯差異,吸煙、飲酒、非酒精性脂肪肝發(fā)病率差異無統(tǒng)計學意義,甘油三酯、高密度脂蛋白膽固醇、alt和超敏c反應蛋白差異無統(tǒng)計學意義。2全部研究對象中l(wèi)dl-c指標達標118例(低密度脂蛋白膽固醇比基線降低50%或者ldl-c降至1.80mmol/l,達標率22.50%),其中l(wèi)dl-c比基線降低50%的82例(達標率15.60%),ldl-c降至1.80mmol/l的76例(達標率14.50%)。與劑量增加組比較,在初始治療組的研究人群中的ldl-c達標率更高(25.10%vs.17.10%,p=0.04),但是ldl-c水平達到1.80mmol/l(70mg/dl)或者ldl-c水平降低50%的單一指標差異無統(tǒng)計學意義。初始治療組和劑量增加組患者的ldl-c、crp在隨訪過程中均有所下降[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全部研究人群共計報告他汀類藥物肌肉癥狀(statinassociatedmusclesymptoms,sams)37例(發(fā)病率7.00%),其中肌肉疼痛19例(發(fā)病率3.60%)、肌肉僵硬21例(發(fā)病率4.00%)、肌肉無力5例(發(fā)病率1.00%);cpk升高≥正常上限5倍患者18例(發(fā)病率3.40%);alt升高≥正常上限3倍患者9例(發(fā)病率1.70%);符合終點事件診斷標準而停用阿托伐他汀的24例(發(fā)病率4.60%),其中2例(發(fā)病率0.38%)同時出現(xiàn)肌肉癥狀、cpk升高≥正常上限5倍以及alt升高≥正常上限3倍的情況。大多數(shù)(55.20%)的阿托伐他汀相關不良反應出現(xiàn)在阿托伐他汀開始治療或者劑量增加后的1個月內。501例(95.40%)患者在最后一次隨訪后,仍在繼續(xù)高強度阿托伐他汀治療。與劑量增加組比較,在初始治療組的研究人群中報告的阿托伐他汀相關的肌肉癥狀患者比例較高(8.70%vs.3.50%,P=0.03)及總的終點事件比例較高(5.60%vs.2.40%,P=0.04)。阿托伐他汀相關的單一不良反應如肌肉疼痛、肌肉僵硬、肌肉無力、CPK升高≥正常上限5倍、消化道癥狀、ALT升高≥正常上限3倍檢出率組間比較差異無統(tǒng)計學意義。4全部研究人群的ALT水平在隨訪2周及1月時較基線水平升高[28.50(23.37,35.40)vs.31.10(24.55,41.85),28.72(22.50,40.73)。P值均0.01],隨訪3月時檢測結果與基線水平比較差異無統(tǒng)計學意義;CPK水平于隨訪1月及3月時較基線水平升高[68.00(56.00,82.00)vs.72.86(47.47,99.75),69.33(53.49,90.35)。P值均0.01]。在分組觀察,初始治療組人群的ALT水平在隨訪2周及1月、3月時較基線水平均升高[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水平于隨訪1月及3月時較基線水平升高[69.00(58.00,84.00)),78.38(56.72,103.08),72.28(56.22,92.52),P值均0.01]。劑量增加組人群的ALT水平在隨訪2周、1月時較基線水平均升高[28.00(23.19,35.30)vs.30.55(23.40,40.01),31.12(22.79,40.96)。P值均0.01),但是在隨訪3月時與基線水平比較差異無統(tǒng)計學意義;CPK水平在隨訪2周及1月、3月時與基線水平比較差異均無統(tǒng)計學意義。結論:高強度阿托伐他汀治療后研究對象的LDL-C、CRP水平下降,初始治療組的LDL-C水平達標率高于劑量增加組。初始治療組的相關肌肉癥狀及終點事件比例高于劑量增加組。
[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.

【學位授予單位】：河北醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R54

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