| 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. |
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