The Clinical Study On The Treatment Of Atorvastatin Combined With Ezetimibe In Patients With Acute Coronary Syndrome

BackgroundAtherosclerosis is one of the most significant risk factors for cardiovascular disease. Low density lipoprotein cholesterol (LDL-C) is the main component in blood lipid for the cause of atherosclerosis. Epidemiological, clinical and basic research have shown that LDL-C is closely related to the occurrence and development of atherosclerosis. In recent years, research results have strongly demonstrated that reasonable and effective lipid adjusting treatment can significantly reduce the risk of adverse cardiovascular events for hyperlipidemia patients or high risk group people with atherosclerosis disease, so blood lipid level is considered as the core strategy of prevention and treatment of cardiovascular disease.Atherosclerosis is a pathological process involving multiple factors. In recent years, studies have shown that atherosclerosis is on the basis of chronic inflammation of the arteries. Vascular endothelial dysfunction, oxidative stress are involved in the process. They influence and interact with each other, leading to constant development of the disease. Among many inflammatory factors, hsCRP is closely related to the development of atherosclerosis. It can affect the stability of atherosclerosis (AS) plaque. And as endothelial diastole and contraction factor, nitric oxide and endothelin influence endothelial function and also play a key role in the process of atherosclerosis. Matrix metalloproteinase9(MMP-9) can degrade the main components of vascular basement membrane and the fibrous cap, and stimulate the continuous development of atheromatous plaque.Statins have been confirmed in more than10years of clinical practice that it can effectively reduce the level of LDL-C for dyslipidemia patients. At the same time, statins have numerous functions such as inhibiting vascular smooth muscle cell proliferation, improving endothelial cell function, enhancing fibrinolytic activity, stabilizing atherosclerotic plaque, and inhibiting inflammation, thus significantly reducing cardiovascular occurrence rate and mortality in patients with atherosclerosis. However, the level of LDL-C still cannot reach bellow the target, although many patients take large doses of statin. LDL-C target rate is still low for patients with high-risk of cardiovascular disease, so patiengs with coronary heart disease must take more effective drug for intervention of dyslipidemia.Ezetimibe is a kind of cholesterol absorption inhibitor. It can selectively inhibit intestinal type C Niemann Peak ProteinClL1(NPC1L1) activity, reduce the intestinal absorption of cholesterol, and reduce plasma cholesterol levels and liver cholesterol reserves. Research shows that the drug can reduce the intestinal absorption of cholesterol by more than50%. In recent years, studies have shown that Atorvastatin together with Ezetimibe can further reduce the LDL-C level by6%-25.8%, significantly increase the success rate of achieving the goal of lowering the blood lipid, and there is no significant difference in the adverse reaction rate from using statins alone. The safety and tolerance of using the medication are good. Excepting from benefiting the blood lipid indexes, Ezetimibe can also inhibit oxidative stress reaction, increase endothelial nitric oxide synthase expression, improve the elasticity of the arteries, and inhibit vascular inflammation, etc.Purpose1. To explore whether the combination of Ezetimibe and atorvastatin can further reduce the lipid level in patients with acute coronary syndrome.2. To explore whether combination treatment can further reduce the level of plasma inflammatory markers in patients with acute coronary syndrome. Methods1. SubjectsThis study use a randomized, prospective, double-blind, placebo-controlled method.74patients with acute coronary syndromes are randomly divided into atorvastatin treatment group (using atorvastatin alone, n=37) and joint treatment group (atorvastatin and ezetimibe, n=37).The treatment lasts for12months.2. Drug applicationAll patients take antiplatelet drugs and lipitor (Pfizer,20mg/day). Diabetic patients are given glucose-lowering drugs. Joint treatment group, on the basis of the routine treatment, are given Ezetimibe (Merck,10mg/day).3. Laboratory testsBefore and after12months of treatment, each patient’s liver and kidney function, blood lipids, myocardial enzyme spectrum, glycosylated hemoglobin, high-sensitivity c-reactive protein (hsCRP), nitric oxide (NO), endothelin1(ET1), MMP9levels were tested. Liver and kidney function, blood lipids and hsCRP are tested by Hitachi7600automatic biochemical analyzer. Glycosylated hemoglobin protein is tested by affinity chromatography method. NO is tested by Nitrate reductase method, and the testing kits are bought from Nanjing Jiancheng biology Co, Ltd. ET1, MMP-9are tested by EILSA method. ET-1kits are purchased from Beijing Eastern Biological Technology Co. LTD. MMP-9kits are purchased from R and D SYSTEM of America.4. Major cardiovascular eventsDuring the followed-up12months the occurrence rate of major adverse coronary incidents of all patients were observed and statisticed. Major adverse coronary events includes unstable angina, nonfatal myocardial infarction, sudden cardiac death and coronary reascularization. Coronary reascularization includes coronary artery bypass surgery(CABG) and primary percutaneous coronary interention (PCI).Results1. The clinical characteristics of two group patients The two group patients have similar baseline characteristics, including age, sex, body mass index, blood pressure, blood fat level, history of smoking, basic medication administration and history of diabetes, etc.2. Comparison of blood lipid levels of two group patientsBefore treatment, the blood lipid baseline levels of these two groups have no significant difference. After treatment for12months, the serum total cholesterol (TC), LDL-C, triglyceride (TG) level of the two groups patients significantly decreased and high density lipoprotein cholesterol (HDL-C) level markedly increased than before. The differences are statistically significant. After treatment for12months, the difference of the serum LDL-C level in joint treatment group is more significant. After treatment for12months, the serum LDL-C level in the combined treatment group has decreased more significantly compared with the Atorvastatin treatment group.3. Comparison of the inflammatory factor levels of the two group patientsBefore the treatment, MMP-9, hsCRP, NO, ET1levels of two groups have no significant difference. After treatment for12months, the serum levels of MMP-9, hsCRP, ET1of the two groups are significantly lower than before, while the serum level of NO increases significantly. After treatment, the difference of serum levels of hsCRP, MMP-9, NO, ET1in the joint treatment group is more significant. Comparing the two groups after treatment, the serum hsCRP, MMP-9, NO, ET1levels in the joint treatment group have changed more significantly than the atorvastatin treatment group.4. Comparison of major cardiovascular eventsDuring the follow-up12months, the main coronary adverse event rate in the atorvastatin treatment group is4/36(11.1%) and3/36(8.3%) in the combination treatment group. The coronary reascularization rate in the atorvastatin treatment group is3/36(8.3%) and2/36(5.7%) in the joint treatment group.Conclusion 1. This study has confirmed that ezetimibe, on the basis of atorvastatin, further reduces the level of LDL-C.2. Except from lowering lipid, ezetimibe can further reduce plasma MMP-9, hsCRP, ET1levels and increases NO level in patients with acute coronary syndrome. BackgroundCoronary atherosclerotic heart disease is a serious threat to human health. Studies have shown that local rupture of atherosclerosis plaque and thrombosis are the leading cause of acute cardiovascular events. Therefore, research on the mechanism, detection means and intervention strategy of vulnerable plaques has become a hot spot in clinical cardiology in recent years. At present, the early detection of vulnerable plaques is mainly based on angiography, intravascular ultrasound, optical coherence tomography inspection means. These detection method have such shortcomings as great trauma and higher cost. Because the process of converting atherosclerotic plaque from stability to delicacy involves inflammation, metabolism, blood coagulation, immunity, and other links, it needs a comprehensive evaluation from the morphology of the plaques to the body’s inflammatory response, endothelial function, and collagen network status.Ultrasonic detection of carotid plaques has such advantages as economy, noninvasive, high repeatability, etc. The increase of carotid intima-media thickness is the noninvasive evaluation indicator of early atherosclerosis, and is also the important risk factor and predictor of cardio-cerebrovascular disease. In addition, the plaque echo, plaque area and volume, eccentric plaque index are also closely associated with the occurrence of acute coronary syndrome.Vascular endothelium is not only a mechanical barrier protection of vascular smooth muscle, but also an important endocrine organ. The vascular endothelial cells adjust the vascular stability, maintain vasodilatation and contraction, inhibit or promote the proliferation and migration of vascular smooth muscle cell, promote thrombosis or fibrinolysis, and promote the inter-balance of antioxidant and oxidation action. Endothelial dysfunction is not only a precipitating factor for early atherosclerosis, but also plays an important role in the development of atherosclerotic plaque.Statins is the cornerstone to cure coronary heart disease. Except from reducing lipid, it can also reduce inflammation, improve endothelial function, and oxidative stress, inhibit thrombosis and other multiple effects. But statins alone cannot make the blood fat of certain coronary heart disease patients reach the standard. While double doses of statins increase the rate of adverse events of drugs. Therefore, for coronary heart disease patients and high risk group people, it calls for the joint treatment to make blood fat reach the standard so as to reduce the risk of acute cardiovascular events.Ezetimibe is a kind of new inhibitor to decrease cholesterol absorption, and it plays its role through selectively inhibiting the activity of intestinal type C NPC1L1. Study has proved that the complementation of ezetimibe and statins can play a more powerful role in lipid-lowering, and ezetimibe can metabolize without cytochrome P450enzymes. It seldom interacts with other medications, thus is well tolerated and safe.Recent studies have proved that besides adjusting lipid, ezetimbe can also promote the vasodilatation of acetylcholine mediate, improve oxidative stress reaction, delay the development of atherosclerosis, increase the expression of endothelial nitric oxide synthase, and inhibit vascular inflammation, and so on. But it is unclear whether these effects can translate into clinical benefit.Therefore, this study adopts the randomized, double-blind, and prospective method. It observes that on the basis of statin therapy, whether Ezetimibe can further improve endothelial function, decrease the carotid intima-media thickness (CIMT), reduce the instability of carotid plaques, thus delay the process of carotid atherosclerotic plaques. Purpose1. To explore whether joint lipid adjusting treatment can further improve endothelial function in patients with acute coronary syndrome.2. To explore whether joint lipid adjusting treatment can reduce the carotid intima-media thickness, decrease plaque areaMethods1. SubjectsThis study is a randomized, prospective, double-blind, placebo-controlled trial.74patients of acute coronary syndrome are randomly divided into Atorvastatin treatment group (using Atorvastatin alone, n=37) and joint treatment group (Atorvastatin and Ezetimibe, n=37). The treatment lasts for12months.2. Drug applicationAll patients take antiplatelet drgus and lipitor (Pfizer,20mg/day). Diabetic patients are given glucose-lowering drugs. Joint treatment group, on the basis of the routine drug treatment, are given Ezetimibe (Merck,10mg/day).3. Determination of brachial artery flow mediate diastolic function (FMD)According to Celermajer method, the patients rest for10minutes before the test, and outreach their right upper limb by15°. The detecting target is the brachial artery4cm above the elbow. It callls for synchronously recording electrocardiogram (ECG), and in the left ventricular end-diastolic (synchronously ECG displaying R wave) measuring the vertical distance of the front and rear membrane of the brachial artery. It needs to measure three cardiac cycles each time, and take the average figure as the basic brachial artery diameter (DO). Then it needs to place the sphygmomanometer cuff in the elbow, inflate pressure by300MMHG, deflate it after4minutes, and60-90seconds after deflating measure the brachial artery diameter (D1). It takes the change of the brachial artery diameter after reactive hyperemia (D1-D0)/D0*100%to represent the brachial artery endothelium dependent vasodilatation function.4. Carotid ultrasound measurement ALOKAα10color doppler ultrasound instrument, whose probe center frequency is5-11hz, is used to detect patients with bilateral common carotid artery before and after12months of treatment respectively, the intima-media thickness(IMT) of the carotid artery bifurcation and internal carotid artery after the initial period of1cm are observed too. At the same time the pipe diameter, plaque area were calculated. The two sides are measured3times each, and the average figure are taken. This research defines the atheromatous plaque as IMT values≥1.5mm. Plaque area calculation:in the horizontal and vertical axis carotid artery section area was measured by plethysmographic measurement method, respectively.Results1. Comparison of brachial artery flow mediated diastolic dysfunctionBefore treatment, no obvious difference is found between the FMD of the two groups. After treatment for12months,two groups of FMD is obviously improved, and the FMD in the joint treatment grpup has improved more obviously. Comparing the two groups after treatment, the FMD in the joint treatment group has improved more obviously.2. Comparison of carotid intima thickness and carotid artery diameterBefore treatment, CIMT and carotid artery diameter of the two groups have no significant difference. After treatment for12months, CIMT of the two groups has significantly lowered. CIMT in the joint treatment group has decreased more significantly. Comparing the two groups after treatment, the CIMT decrease statistically in the joint treatment group than in the Atorvastatin treatment group.3. Comparison of the area of carotid plaquesBefore treatment, there is no significant difference in area of carotid plaques between the two groups. After treatment for12months, the plaque area has decreased significantyly. While comparing the two groups after treatment, the plaques area has no significantly difference. Conclusion1. The combination treatment can improve brachial artery flow mediate diastolic function in patients with acute coronary syndrome.2. The combination treatment can reduce the carotid intima thickness in patients with acute coronary syndrome.3. After treatment the plaque area were reduced in patients with acute coronary syndrome.