【作者】 闫杰；

【导师】 安丰双；

【作者基本信息】 山东大学 ， 内科学（心血管病）（专业学位）， 2023， 硕士

【摘要】 研究背景血脂异常是动脉粥样硬化性心血管病(Atherosclerotic cardiovascular disease,ASCVD)的独立危险因素之一。通常认为,低密度脂蛋白胆固醇(Low-density lipoprotein cholesterol,LDL-C)是降脂治疗最重要的干预靶点。然而,已有研究显示,即使单独或者联合使用他汀类药物、依折麦布、前蛋白转化酶枯草溶菌素kexin-9型抑制剂进行高强度持续降LDL-C治疗,甘油三酯水平高的患者ASCVD的发生风险仍然很高,因此,甘油三酯水平升高被认为是ASCVD的“风险增强因素”。Omega-3 多不饱和脂肪酸(Omega-3 Polyunsaturated Fatty Acids,N-3 PUFA)是一类重要的必需脂肪酸,包括α-亚麻酸(α-linolenic acid,ALA)、二十碳五烯酸(Eicosapentaenoic acid,EPA)和二十二碳六烯酸(Docosahexaenoic acid,DHA)等,参与多种生物代谢过程。通过抑制肝脏合成与分泌极低密度脂蛋白和甘油三酯,增加外周组织甘油三酯清除率来降低血浆中甘油三酯水平,并且具有抗炎、抗栓、稳定动脉粥样硬化斑块、血管内皮保护、抗氧化等多种作用。目前N-3 PUFA已被广泛用于高甘油三酯血症的治疗,但近年来的多项大型随机对照试验就其能否带来心血管获益显示出矛盾的结果。研究目的通过Meta分析系统评价N-3 PUFA预防心血管疾病的疗效与安全性,为临床提供循证医学证据。研究方法本研究的设计遵循PRISMA关于系统评价和Meta分析的声明。截至2022年11月,我们全面检索中文数据库和英文数据库中关于N-3 PUFA预防心血管疾病疗效与安全性的随机对照试验。使用Cochrane偏倚风险工具对纳入研究的方法学质量进行独立评估。使用相对危险度(Relative risk,RR)进行综合效应评估,置信区间(Confidence interval,CI)为95%。采用双侧P值,如果P<0.05为结果显著,具有统计学意义。采用Higgins I2统计量来评估统计异质性。采用随机效应模型来分析各研究的相对风险。根据N-3 PUFA种类、人群特征的差异进行亚组分析。通过敏感性分析、亚组分析、Meta回归来寻找异质性的潜在来源。使用Meta回归模型探索性分析N-3 PUFA剂量(g/day)与各结局之间的线性关系。发表偏倚用Egger回归、Harbord加权线性回归法检验漏斗图的不对称性。使用GRADE系统为每个结果进行证据质量和推荐强度分级。研究结果1.本研究共有15篇文献符合纳入标准,均为随机对照研究,共计141164名参与者,其中70650人被分配到N-3 PUFA组,70514人被分配到对照组(安慰剂)。平均随访时间为4.2年。所有研究的方法学质量评价均为低偏倚风险。2.在主要疗效结局终点方面,与安慰剂组相比,使用N-3 PUFA可以降低主要心血管事件(Major cardiovascular events,MACE)(RR 0.95,95%CI 0.91～0.99;P=0.03)、心肌梗死(Myocardial infarction,MI)(RR 0.90,95%CI 0.83～0.99;P=0.02)、心血管死亡(RR 0.94,95%CI 0.88～0.99;P=0.03)的风险;增加心房颤动(Atrial fibrillation,AF)(RR 1.25,95%CI 1.10～1.41;P=0.00)的风险;不能降低心力衰竭(Heart failure,HF)(RR 0.97,95%CI 0.86～1.09;P=0.58)、卒中(RR 1.05,95%CI 0.96～1.16;P=0.27)、全因死亡(RR 0.98,95%CI 0.94～1.02;P=0.30)的风险。3.在安全性结局终点方面,与安慰剂组相比,使用N-3 PUFA不增加胃肠道不适(RR 1.19,95%CI 0.95～1.50;P=0.13)、出血相关疾病(RR 1.11,95%CI 0.95～1.30;P=0.17)、癌症(RR 1.03,95%CI 0.98～1.09;P=0.20)的风险。4.根据N-3 PUFA剂型进行的亚组分析显示,与安慰剂组相比,二十碳五烯酸乙酯可以降低 MACE(RR 0.79,95%CI 0.73～0.85)、MI(RR 0.72,95%CI 0.62～0.82)、心血管死亡(RR 0.82,95%CI 0.67～0.99)的风险;增加 AF(RR 1.35,95%CI 1.11～1.65)、出血相关疾病(RR 1.50,95%CI 1.13～1.99)的风险。Omega-3酸乙酯可以降低心血管死亡(RR 0.93,95%CI 0.88～0.99)的风险;增加AF(RR 1.12,95%CI 1.03～1.21)的风险。鱼油膳食补充剂、Omega-3羧酸不能降低MACE、MI、心血管死亡的风险,但均增加了 AF风险。5.根据人群特征进行的亚组分析显示,对于一般人群,与安慰剂相比,使用 N-3 PUFA 可以降低 MI(RR 0.83,95%CI 0.70～0.99)的风险;增加 AF(RR 1.12,95%CI 1.01～1.26)的风险。对于有高危因素或已经确诊患有心血管疾病的患者,与安慰剂相比,使用N-3 PUFA可以降低MACE(RR 0.91,95%CI 0.83～0.99)的风险;增加AF(RR 1.29,95%CI 1.08～1.55)的风险。对于既往MI的患者,与安慰剂相比,使用N-3 PUFA不能降低MACE、MI、心血管死亡的风险;增加 AF(RR 1.88,95%CI 1.02～3.48)、卒中(RR 1.32,95%CI 1.04～1.68)的风险。6.Meta回归显示N-3 PUFA剂量是主要心血管事件(R2=78.43%)、心肌梗死(R2=41.70%)、心房颤动(R2=100%)的异质性来源之一。在检验N-3PUFA剂量与主要心血管事件风险之间的线性关联Meta回归模型中,在0.84 g/d～3.84 g/d N-3 PUFA 剂量范围内,每增加 1 g/d N-3 PUFA 剂量,RR 为 0.96(95%CI 0.94～0.98,P=0.00)。在检验N-3 PUFA剂量与心肌梗死之间的线性关联Meta回归模型中,在0.84 g/d～3.84 g/d N-3 PUFA剂量范围内,每增加1 g/d N-3 PUFA剂量,RR 为 0.93(95%CI 0.89～0.98,P=0.01)。在检验 N-3 PUFA 剂量与心房颤动之间的线性关联Meta回归模型中,在0.84 g/d～3.84 g/d N-3 PUFA剂量范围内,每增加 1 g/d N-3 PUFA 剂量,RR 为 1.12(95%CI 1.06～1.18,P=0.00)。7.除心房颤动结局外均未检测出明显发表偏倚,房颤结局的漏斗图不对称,Harbord加权线性回归法所得P=0.03,提示存在发表偏倚,使用剪补法对合并的结果进行调整,结果未发生变化,校正后RR=1.23(95%CI 1.09～1.38)。8.采用GRADE质量评价标准评估证据可信度,由于异质性的表现,主要心血管事件、心肌梗死、心力衰竭、心房颤动、出血相关风险结局降级为中等证据,胃肠不良反应降级为低级别证据,其余结局均为高级别证据。研究结论1.补充N-3 PUFA可以降低主要心血管事件、心肌梗死、心血管死亡风险,但并不是所有种类的N-3 PUFA均可以带来心血管获益。目前的证据支持使用二十碳五烯酸乙酯降低高危患者主要心血管事件、心肌梗死、心血管死亡风险,支持使用Omega-3酸乙酯降低心血管死亡风险,不支持使用鱼油膳食补充剂、Omega-3羧酸预防心血管疾病。2.所有种类的N-3 PUFA补充剂均可能会剂量依赖性的增加心房颤动的发生风险。3.N-3 PUFA的剂量可能与主要心血管事件、心肌梗死的风险呈负相关,与心房颤动的风险呈正相关。4.N-3 PUFA补充剂具有良好的安全性和耐受性,但是二十碳五烯酸乙酯可能增加出血风险,与抗血小板药物或抗凝药同服时应定期进行监测。更多还原

【Abstract】 BackgroundDyslipidemia is one of the independent risk factors for atherosclerotic cardiovascular disease(ASCVD).It is generally accepted that low-density lipoprotein cholesterol(LDL-C)is the most important target of intervention for lipid-lowering therapy.However,patients with high triglyceride(TG)levels were at high risk for ASCVD even when treated with statins alone or in combination with ezetimibe,PCSK-9 inhibitor for high-intensity sustained LDL-C lowering.Now,elevated TG level is considered to be a "risk-enhancing factor" for ASCVD.Omega-3 polyunsaturated fatty acids(N-3 PUFA)are an important class of essential fatty acids involved in a variety of biological metabolic processes,including α-linolenic acid(ALA),eicosapentaenoic acid(EPA)and docosahexaenoic acid(DHA).It can reduce plasma TG levels by inhibiting the synthesis and secretion of very low-density lipoprotein and TG in the liver and increasing TG clearance in peripheral tissues,and has various effects such as anti-inflammatory,anti-thrombotic,atherosclerotic plaque stabilization,vascular endothelial protection and antioxidant.N-3 PUFA has been widely used in the treatment of hypertriglyceridemia,but several large randomized controlled trials in recent years have shown conflicting results regarding its ability to provide cardiovascular benefits.ObjectivesEvaluate the efficacy and safety of N-3 PUFA for the prevention of cardiovascular disease through a meta-analysis to provide clinical evidence for evidence-based medicine.MethodsThe design of this study followed the PRISMA statement on the systematic evaluation and meta-analysis.As of November 2022,we comprehensively searched English databases and Chinese databases for randomized controlled trials on the efficacy and safety of N-3 PUFA for the prevention of cardiovascular disease.The methodological quality of included studies was independently assessed using the Cochrane Risk of Bias Tool.Pooled effects were assessed using relative risk(RR)with a confidence interval(Cl)of 95%.A two-sided P value was used,and results were considered statistically significant if P<0.05.The Higgins I2 statistic was used to assess statistical heterogeneity.A random-effects model was used to analyze the relative risk across studies.Subgroup analysis was performed based on differences in N-3 PUFA type and population characteristics.Sensitivity analysis,subgroup analysis,and meta-regression were used to find potential sources of heterogeneity.Meta-regression models were used to explore the linear relationship between N-3 PUFA dose(g/day)and each outcome.Publication bias was examined by Egger regression,Harbord weighted linear regression to test the asymmetry of the funnel plot.Quality of evidence and strength of recommendation grading was performed for each outcome using the GRADE system.Results1.Fifteen randomized controlled trials with a total of 141,164 participants were included in this study,of which 70,650 were assigned to the N-3 PUFA group and 70,514 were assigned to the control group(placebo).The mean follow-up time was 4.2 years.The methodological quality of all trials was low risk of bias.2.In terms of the primary efficacy endpoint,the use of N-3 PUFA reduced the risk of major cardiovascular events(MACE)(RR 0.95,95%CI 0.91 to 0.99;P=0.03),MI(RR 0.90,95%CI 0.83 to 0.98;P=0.02),and cardiovascular death(RR 0.94,95%CI 0.88 to 0.99;P=0.03)compared with placebo.However,the risk of atrial fibrillation(AF)(RR 1.25,95%CI 1.10 to 1.41;P=0.00)was significantly increased.The risks of heart failure(HF)(RR 0.97,95%Cl 0.86 to 1.09;P=0.58),stroke(RR 1.05,95%CI 0.96 to 1.16;P=0.27),and all-cause death(RR 0.98,95%CI 0.94 to 1.02;P=0.30)were not statistically significantly different between the two groups.3.For the safety endpoint,the use of N-3 PUFA did not increase the risk of gastrointestinal problems(RR 1.19,95%Cl 0.95 to 1.50;P=0.13),bleeding-related disorders(RR 1.11,95%CI 0.95 to 1.30;P=0.17),or cancer(RR 1.03,95%CI 0.98 to 1.09;P=0.20)compared with placebo.4.Subgroup analysis based on N-3 PUFA dosage forms showed that the use of eicosapentaenoic acid ethyl ester formulations reduced the risk of MACE(RR 0.79,95%CI 0.73 to 0.85),MI(RR 0.72,95%CI 0.62 to 0.82),and cardiovascular death(RR 0.82,95%Cl 0.67 to 0.99)compared with placebo.However,there was an increased risk of AF(RR 1.35,95%CI 1.11 to 1.65)and bleeding-related diseases(RR 1.50,95%Cl 1.13 to 1.99).Omega-3 acid ethyl ester reduced the risk of cardiovascular death(RR 0.93,95%CI 0.88 to 0.99)and increased AF(RR 1.12,95%CI 1.03 to 1.21).Neither fish oil dietary supplements,nor Omega-3 carboxylic acid reduced the risk of MACE,MI,or cardiovascular death,but all increased the risk of AF.5.Subgroup analysis based on population characteristics showed that for the general population,the use of N-3 PUFA reduced the risk of MI(RR 0.83,95%CI 0.70 to 0.99)and increased the risk of AF(RR 1.12,95%CI 1.01 to 1.26)compared to placebo.For patients with high-risk factors or already diagnosed with cardiovascular disease,use of N-3 PUFA reduced the risk of MACE(RR 0.91,95%CI 0.83 to 0.99)and increased the risk of AF(RR 1.29,95%CI 1.08 to 1.55)compared with placebo.In patients with prior MI,the use of N-3 PUFA did not reduce the risk of MACE,MI,or cardiovascular death,but increased the risk of AF(RR 1.88,95%CI 1.02 to 3.48),and stroke(RR 1.32,95%CI 1.04 to 1.68),compared with placebo.6.Meta-regression showed that N-3 PUFA dose was one of the sources of heterogeneity for MACE(R2=78.43%),MI(R2=41.70%),and AF(R2=100%).In a linear association meta-regression model testing the association between N-3 PUFA dose and MACE risk,the RR was 0.96(95%CI 0.94 to 0.98,P=0.00)for each 1 g/d increase in N-3 PUFA dose in the range of 0.84 g/d to 3.84 g/d N-3 PUFA dose.In testing the linear association meta-regression model between N-3 PUFA dose and MI,the RR was 0.93(95%CI 0.89 to 0.98,P=0.01)for each 1 g/d increase in N-3 PUFA dose in the range of 0.84 g/d to 3.84 g/d N-3 PUFA dose.In testing the linear association meta-regression model between N-3 PUFA dose and AF,the RR was 1.12(95%CI 1.06 to 1.18,P=0.00)for each 1 g/d increase in N-3 PUFA dose in the range of 0.84 g/d to 3.84 g/d N-3 PUFA dose.7.No significant publication bias was detected except for the AF outcome,and the funnel plot for the AF outcome was asymmetric,with P=0.03 obtained by Harbord weighted linear regression method,suggesting the detection of publication bias,and the results were unchanged when adjusted for the combined results using the trim-and-fill method,with a corrected RR=1.23(95%CI 1.09 to 1.38).8.The GRADE quality evaluation criteria were used to assess the credibility of the evidence,and due to heterogeneity,MACE,MI,HF,AF,and bleeding-related disease risk outcomes were downgraded to moderate evidence,gastrointestinal adverse effects were downgraded to low level evidence,and the remaining outcomes were all high-level evidence.Conclusions1.Supplementation with N-3 PUFA reduces the risk of major cardiovascular events,myocardial infarction,and cardiovascular death,but not all types of N-3 PUFA provide cardiovascular benefits.Current evidence supports the use of eicosapentaenoic acid ethyl ester to reduce the risk of major cardiovascular events,myocardial infarction,and cardiovascular death in high-risk patients and the use of Omega-3 acid ethyl ester to reduce the risk of cardiovascular death.2.All types of N-3 PUFA supplements may dose-dependently increase the risk of atrial fibrillation.3.The dose of N-3 PUFA may be negatively associated with the risk of major cardiovascular events,myocardial infarction,and positively associated with the risk of atrial fibrillation.4.N-3 PUFA supplements have a good safety and tolerability profile,but eicosapentaenoic acid ethyl ester may increase the risk of bleeding and should be monitored regularly when taken with antiplatelet agents or anticoagulants.更多还原