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Cardiovascular Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, PR ChinaKey Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an 710061, PR ChinaKey Laboratory of Molecular Cardiology, Shaanxi Province, PR China
Cardiovascular Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, PR ChinaKey Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an 710061, PR ChinaKey Laboratory of Molecular Cardiology, Shaanxi Province, PR China
Cardiovascular Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, PR ChinaKey Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an 710061, PR ChinaKey Laboratory of Molecular Cardiology, Shaanxi Province, PR China
Statin therapy plays an important role in stabilizing and regressing coronary artery plaques. Omega-3 supplements also have anti-inflammatory and antioxidant effects on coronary plaques. However, the effect of omega-3 supplementation on the basis of statin therapy on the stability and composition of plaques, is still unclear. We searched for randomized controlled trials published prior to November 2020 in the PubMed, Embase and Cochrane databases. Finally, eight studies using different imaging techniques to evaluate coronary atherosclerotic plaque, including optical coherence tomography (OCT), coronary CT angiography (cCTA) and intravascular ultrasound (IB-IVUS), met our inclusion criteria. We pooled data extracted from the included studies using the standardized mean difference (SMD) or mean difference (MD) of the random effects model. Compared with statin treatment alone, the combined treatment further delayed the progression of total plaque volume [SMD -0.36, 95% confidence interval (CI) -0.64 to -0.08, p = 0.01] and fiber content (SMD -0.40, 95% CI -0.68 to -0.13, p = 0.004). The plasma high-sensitivity C-reactive protein (hs-CRP) level of patients in the combination treatment group was significantly lower than that of the patients in the statin treatment group alone (SMD -0.30, 95% CI -0.59 to -0.01, p = 0.04). In addition, the combined use of omega-3 further increases the fibrous cap thickness (FCT) of the plaque with an MD of 29.45 μm. There were no significant differences in plasma high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), or lipid content in plaques between the two groups. Omega-3 combined with statins is superior to the statin treatment group in stabilizing and promoting coronary plaque regression and may help to further reduce the occurrence of cardiovascular events.
Unstable coronary plaques, which are characterized by thin fibrous caps, large lipid pools, and infiltration of macrophages,
Histopathologic characteristics of atherosclerotic coronary disease and implications of the findings for the invasive and noninvasive detection of vulnerable plaques.
are the main cause of major adverse cardiovascular events. The progression of coronary plaque is also closely related to the high incidence of cardiovascular events.
Effect of atorvastatin therapy on fibrous cap thickness in coronary atherosclerotic plaque as assessed by optical coherence tomography: the EASY-FIT study.
. Previous studies have shown that long-term intake of long-chain n-3 polyunsaturated fatty acids (PUFAs) can reduce the incidence of cardiovascular events.
Therefore, as an adjuvant treatment of statins, omega-3 may have potential benefits for the residual risks of statins. However, it is still unclear whether combination therapy is better than statin therapy alone in terms of plaque stability and progression. Therefore, we conducted a meta-analysis of the effects of omega-3 on plaque composition and progression based on statin therapy.
Methods
The meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
We searched the following databases for English-related research published prior to November 2020: PubMed (MEDLINE), The Cochrane Library, and Embase. An example search strategy for PubMed is available in Table S1. The study protocol was registered with PROSPERO (CRD42020222439).
We included articles that met the following criteria: (1) the studies must be conducted among adults (≥18 years) with a diagnosis of coronary artery disease or known coronary atherosclerosis; (2) the effect of statins combined with omega-3 on coronary arterial plaque was compared with statin therapy; (3) atherosclerosis was considered the relevant outcome, and the percent or absolute change in coronary atherosclerosis between baseline and follow-up was reported; (4) randomized controlled research with a follow-up period ≥6 months; and (5) published articles with the full text available in English.
Meanwhile, the exclusion criteria were as follows: (1) subjects who had atherosclerosis in other parts besides the coronary artery; (2) review, meeting abstract, meta-analysis or clinical trials with unpublished full text; and (3) insufficient endpoint data.
Two authors selected the studies in accordance with the inclusion criteria and conducted the data extraction. The following data were extracted: (1) basic information about the included study, i.e., author, year of publication, and country where the study was conducted; (2) patient demographics, such as age, sex, medication, and risk factors for cardiovascular disease, medication and target vessel; and (3) trial characteristics, such as the number of subjects, dose and type of omega-3 and statin, duration of follow-up and study design. (4) relevant clinical outcomes. Any disagreement was resolved by panel discussion until consensus was reached or by consulting a senior author.
The primary endpoint was the pre-postintervention change in total plaque volume. The secondary endpoint was defined as changes in fibrous and lipid volume of coronary plaque from baseline to follow-up, the pre-postintervention change in fibrous cap thickness (FCT) and the concentrations of high-sensitivity C-reactive protein (hs-CRP), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C).
Two reviewers evaluated the quality of the selected studies according to the Cochrane Collaboration's tool for randomized controlled trials. The evaluation items of each included study were divided into three categories: low risk of bias, unclear risk of bias and high risk of bias. The following characteristics were evaluated: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other biases. The details of the risk of bias in all included studies are presented in Figure S1. Any discrepancy was resolved by discussion until consensus was reached or by consulting a senior author.
Figure 1PRISMA flow chart of meta-analysis. PRISMA = preferred reporting items for systematic reviews and meta-analyses.
Some studies reported results in the form of medians and interquartile ranges instead of the mean and standard deviation, so we adopted the methods of Luo D et al. and Wan X et al. to convert the data.
The standardized mean difference (SMD) or mean difference (MD) for random effects models was used in the statistical analysis. Between-study heterogeneity was assessed for all endpoints with the I2 statistic. According to the Cochrane handbook, heterogeneity was categorized as nonimportant (I2<40%), moderate (30%<I2<60%), substantial (60%<I2<90%) and nonnegligible (75%<I2<100%). The forest plot was used to evaluate the results, which were expressed as SMD or MD with 95% confidence intervals (CI) for the main outcome and secondary outcomes. Statistical significance was defined as a two-sided P-value < 0.05. Due to the existence of significant heterogeneity in two secondary endpoints (I2>90%), sensitivity analysis was conducted to ensure the results of the meta-analysis by removing the first and second influential studies. In addition, potential publication bias was assessed by a funnel plot for meta-analysis. According to the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0,
when the included study had two intervention groups, we split the “shared” control group into two groups with a smaller sample size and included two (reasonably independent) comparisons. However, when a study has several independent comparisons with no intervention group in common, we regarded it as coming from different studies and subjected it to meta-analysis. All statistical analyses were conducted with Cochrane Review Manager 5.4.
Results
A total of 356 reports were retrieved from the electronic search. We read the full text of 25 studies after excluding duplicate records and screening the titles and abstracts. Of these 25 studies, 17 records were excluded for various reasons, and 8 studies including 803 subjects met our inclusion criteria (Figure 1).
Concomitant use of Rosuvastatin and Eicosapentaenoic acid significantly prevents native coronary atherosclerotic progression in patients with in-stent neoatherosclerosis.
Effects of the addition of eicosapentaenoic acid to strong statin therapy on inflammatory cytokines and coronary plaque components assessed by integrated backscatter intravascular ultrasound.
Effect of Eicosapentaenoic and Docosahexaenoic acids added to statin therapy on Coronary Artery plaque in patients with Coronary Artery disease: a Randomized Clinical Trial.
Effect of n-3 polyunsaturated fatty acids on regression of Coronary Atherosclerosis in statin treated patients undergoing percutaneous coronary intervention.
Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial.
Of these participants, 421 (52.4%) received combination therapy with statins and omega-3, and 382 (47.6%) received statin therapy alone. Details of patient demographics are presented in Table 1. In the study conducted in Japan, four RCTs used highly purified 1.8 g/d EPA.
Concomitant use of Rosuvastatin and Eicosapentaenoic acid significantly prevents native coronary atherosclerotic progression in patients with in-stent neoatherosclerosis.
Effects of the addition of eicosapentaenoic acid to strong statin therapy on inflammatory cytokines and coronary plaque components assessed by integrated backscatter intravascular ultrasound.
Effect of Eicosapentaenoic and Docosahexaenoic acids added to statin therapy on Coronary Artery plaque in patients with Coronary Artery disease: a Randomized Clinical Trial.
Effect of n-3 polyunsaturated fatty acids on regression of Coronary Atherosclerosis in statin treated patients undergoing percutaneous coronary intervention.
Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial.
Concomitant use of Rosuvastatin and Eicosapentaenoic acid significantly prevents native coronary atherosclerotic progression in patients with in-stent neoatherosclerosis.
Effects of the addition of eicosapentaenoic acid to strong statin therapy on inflammatory cytokines and coronary plaque components assessed by integrated backscatter intravascular ultrasound.
Effect of Eicosapentaenoic and Docosahexaenoic acids added to statin therapy on Coronary Artery plaque in patients with Coronary Artery disease: a Randomized Clinical Trial.
Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial.
Effect of n-3 polyunsaturated fatty acids on regression of Coronary Atherosclerosis in statin treated patients undergoing percutaneous coronary intervention.
Data given as median (interquartile range), mean±SD, n (%). ACS = acute coronary syndrome; BMI = body mass index; CCB = calcium channel blocker; DM = diabetes mellitus; DLP = dyslipidemia; FHx = family history; HTN = hypertension; LAD = left anterior descending; LCX = left circumflex; NR = no reported; RCA = right coronary artery.
Concomitant use of Rosuvastatin and Eicosapentaenoic acid significantly prevents native coronary atherosclerotic progression in patients with in-stent neoatherosclerosis.
Effects of the addition of eicosapentaenoic acid to strong statin therapy on inflammatory cytokines and coronary plaque components assessed by integrated backscatter intravascular ultrasound.
Effect of Eicosapentaenoic and Docosahexaenoic acids added to statin therapy on Coronary Artery plaque in patients with Coronary Artery disease: a Randomized Clinical Trial.
Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial.
Effect of n-3 polyunsaturated fatty acids on regression of Coronary Atherosclerosis in statin treated patients undergoing percutaneous coronary intervention.
Five RCTs reported the absolute or percent change in plaque volume between baseline and follow-up in the included study. We concluded that the combination of omega-3 and statin therapy significantly slowed the progression of coronary plaque volume compared with statin therapy alone (SMD -0.36, 95% CI -0.64 to -0.08, p = 0.01) (Figure 2). Furthermore, we conducted subgroup analysis according to the source of omega-3, the country and the duration of the follow-up. There was no difference in plaque volume changes by the duration of follow-up or the country where the study was conducted (Figure 3). However, the subgroup analysis demonstrated that EPA therapy exhibited a greater reduction (SMD -0.53, 95% CI -1.01 to -0.06) than the combination of EPA and DHA (SMD -0.20, 95% CI -0.42 to 0.02) (Figure 3). Perhaps due to the insufficient sample size, the P value for interaction was not statistically significant (p = 0.21).
Figure 2The forest plot shows the effect of the combination therapy (omega-3+statin) versus statin therapy on the total plaque volume change between baseline and follow-up.
Figure 3(A) Forest plot of subgroup analysis for the source of omega-3 (EPA vs EPA+DHA) reflects the difference in the pre-postintervention change in total plaque volume between the 2 groups. (B) The forest plot of the subgroup analysis for the duration of follow-up (>8 months vs ≤ 8 months) reflects the difference in the pre-postintervention change in total plaque volume between the 2 groups. (C) Forest plot of subgroup analysis for the country where the study was conducted (Japan vs other countries) reflects the difference in the pre-postintervention change in total plaque volume between the 2 groups. CI = confidence interval; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid.
Of 6 studies that reported changes in lipid volume, 2 RCTs used the concept of the lipid volume index, which was defined as the lipid arc multiplied by lipid length.
Concomitant use of Rosuvastatin and Eicosapentaenoic acid significantly prevents native coronary atherosclerotic progression in patients with in-stent neoatherosclerosis.
Overall, the combination of omega-3 and statin therapy was significantly associated with repressing the progression of the lipid volume of coronary plaque compared with statin therapy (SMD -0.96, 95% CI -1.64 to -0.27, p = 0.006) (Figure 4). However, we detected significant heterogeneity among these studies (I2=94%, p < 0.001), so a sensitivity analysis was performed. After excluding the most influential study, the effect of combination therapy became nonsignificant (SMD -0.34, 95% CI -0.69 to 0.01, p = 0.06), with the I2 dropping to 77%. After excluding the second-most influential study, the effect of the combination therapy was still nonsignificant (SMD -0.16, 95% CI -0.41 to 0.08, p = 0.19), with the I2 dropping to 51% (Table 3).
Figure 4(A) The forest plot shows the effect of the combination therapy (omega-3+statin) versus statin therapy on lipid volume changes between baseline and follow-up. (B) The forest plot shows the effect of the combination therapy (omega-3+statin) versus statin therapy on the FCT change between baseline and follow-up. (C) The forest plot shows the effect of the combination therapy (omega-3+statin) versus statin therapy on fibrous volume changes between baseline and follow-up. CI = confidence interval; FCT = fibrous cap thickness.
The fibrous cap thickness (FCT) was measured by OCT. Based on the forest plot, we concluded that the combination therapy was superior to statin therapy in increasing the FCT (MD 29.45 μm, 95% CI 21.67 to 37.23, p < 0.001) (Figure 4).
The change in fibrous volume was reported by 4 RCTs in the included studies. The results showed that there was no significant difference in the fibrous volume of coronary plaque between combination therapy and statin therapy (SMD 0.81, 95% CI -0.22 to 1.84) (Figure 4). Due to the existence of significant heterogeneity (I2=97%, p < 0.001), we also conducted a sensitivity analysis. After removing the most influential study, the combination therapy became significant (SMD -0.40, 95% CI -0.68 to -0.13, p = 0.004) compared with statin therapy, with heterogeneity decreasing significantly (I2=56%, p = 0.08) (Figure 5).
Figure 5The forest plot showing the sensitivity analysis after removing the most influential study reflects the difference in the pre-postintervention change in fibrous volume between the 2 groups. CI = confidence interval.
All included studies reported data on the concentration of HDL-C and LDL-C. Of these studies, 2 RCTs reported the changes in HDL-C and LDL-C concentrations between baseline and follow-up, and the other studies reported the data of follow-up of HDL-C and LDL-C concentrations. Since there was no significant difference in baseline value between the two groups, we included data on pre-postintervention change and follow-up in the meta-analysis. However, there were no significant differences in the concentrations of HDL-C (SMD 0.09, 95% CI -0.05 to 0.23, p = 0.23) and LDL-C (SMD 0.06, 95% CI -0.08 to 0.2, p = 0.41) between the combination therapy and statin therapy (Figures 6).
Figure 6(A) The forest plot shows the effect of the combination therapy (omega-3+statin) versus statin therapy on HDL-C concentration. (B) The forest plot shows the effect of the combination therapy (omega-3+statin) versus statin therapy on LDL-C concentration. (C) The forest plot shows the effect of the combination therapy (omega-3+statin) versus statin therapy on hs-CRP concentration. CI = confidence interval; hs-CRP = high sensitivity C reactive protein; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol.
The level of hs-CRP was also the secondary outcome of interest. Compared with statin therapy, combination therapy was associated with lower hs-CRP concentrations (SMD -0.30, 95% CI -0.59 to -0.01, p = 0.04) (Figure 6).
There was no visible asymmetry in funnel plots, so publication bias was not detected (Figure S2).
Discussion
The current meta-analysis of eight studies evaluated whether combination therapy is more effective than statin therapy alone for stabilizing and promoting regression of coronary plaque. We found that the combination of omega-3 and statins may be superior to statin treatment alone in reducing total plaque volume, fiber volume, serum hs-CRP levels and increasing FCT, but no significant difference in lipid volume and lipid profile was observed between the two treatments.
There is an independent and statistically significant relationship between the size of coronary plaque volume and major adverse cardiovascular events (MACEs).
Relationship between changes in coronary atherosclerotic plaque burden measured by intravascular ultrasound and cardiovascular disease outcomes: a systematic literature review.
The results of our meta-analysis showed that the combination therapy was superior to the statin alone in delaying the progression of plaque. Further analysis revealed that EPA was associated with a smaller coronary plaque volume on the basis of statin treatment. Although high-dose omega-3 has a stronger anti-atherosclerotic effect in Japanese individuals,
the results of our subgroup analysis show that combination therapy does not have a stronger effect of delaying plaque progression in Japanese individuals. In addition, we also conducted a subgroup analysis based on the follow-up time. The results also showed that combination therapy did not further delay the progression of plaques over a longer follow-up period.
Studies have shown that reducing the lipid content of plaques and increasing the content of fiber components are important ways to stabilize plaques.
Our initial results showed that plaque lipid volume was smaller after combined treatment, but there was no significant difference in fiber volume between the two groups. However, due to the significant heterogeneity, we further conducted a sensitivity analysis. After excluding the most influential research, the effect of combined treatment on plaque lipid volume was equivalent to that of statins alone, but it was more effective in slowing down the progression of fiber volume, and the heterogeneity was also significantly reduced. The study of Niki et al. was the main source of heterogeneity in our meta-analysis,
Effects of the addition of eicosapentaenoic acid to strong statin therapy on inflammatory cytokines and coronary plaque components assessed by integrated backscatter intravascular ultrasound.
and its conclusion was significantly different from other studies. Their study may have the following problems: (1) the sample size was insufficient; (2) the follow-up time was the shortest out of all of the included studies; (3) the experimental group received intensive statin intervention for 6 months before taking EPA, which is slightly different from the intervention methods in other studies; (4) the research is a nonblinded RCT.
The meta-analysis also showed that omega-3 did not further reduce the lipid content of plaques based on statin treatment. Studies have shown that the omega-3 treatment group has fewer lipid components in coronary plaques.
Therefore, we believe that the drug-drug interaction may be one of the reasons why the combination therapy does not produce an additive effect.
Our meta-analysis results also showed that the FCT of the combination treatment group increased more. However, we also found that there were fewer fibrous components in the coronary plaques in the combined treatment group. We think this may be caused by the following reasons: (1) The index measurement methods are different. FCT is measured by OCT, while the fiber volume is measured by cCTA and IB-IVUS. (2) The subjects in the FCT study and the fiber volume study are different. The difference in basic levels of EPA and DHA in the plasma of patients among different countries may affect the efficacy of omega-3. (3) The sample size of the study reporting these two outcome indicators is insufficient. (4) Combined treatment significantly slows down the progress of total plaque volume, while the change of fiber volume may decrease with the change of total plaque volume. (5) The potential risk factors are unevenly distributed in the experimental group and the control group, which may play an important role in seemingly contradictory results.
Chronic inflammation also plays an important role in the rupture and progression of coronary atherosclerotic plaques. The level of hs-CRP is commonly used as inflammation markers, which can indirectly reflect the stability of coronary plaques.
We found that compared with statin therapy, the hs-CRP level of combination therapy was significantly reduced. Therefore, we believe that the anti-inflammatory effects of omega-3 may play an important role in combination therapy that stabilizes coronary plaques and slows down the progression of plaque volume and fiber volume.
Studies have shown that an increase in the LDL-C:HDL-C ratio is related to the progression of coronary plaque.
Triglyceride- and cholesterol-rich lipoproteins have a differential effect on mild/moderate and severe lesion progression as assessed by quantitative coronary angiography in a controlled trial of lovastatin.
Our meta-analysis results show that ω-3, as an auxiliary drug for statin therapy, cannot further improve plasma HDL-C and LDL-C levels, which indicates that the beneficial effect of combined therapy on plaque may not be achieved by reducing HDL-C and increasing LDL-C levels.
The present meta-analysis also has several limitations. First, most of these included studies were open-label trials. Second, plaque was measured by various of the techniques, including IVUS, OCT and cCTA, which makes our results have great heterogeneity. Third, the duration of follow-up ranges from 6 months to 30 months, which may affect the observed change in coronary plaque. Fourth, some studies do not specify if the dose of the statins were comparable between the groups. Finally, the differences in the doses and types of omega-3 and statins among studies may affect the results.
To sum up, our meta-analysis suggests that the combination therapy can slow the progression of total plaque volume and fibrous volume more than statin therapy alone. Compared with statin therapy, the combination therapy is associated with a significantly lower plasma hs-CRP and increases FCT.
Disclosures
The study is funded by National Natural Science Foundation of China grant 81941005 (to Dr Z.-Y. Yuan) and the National Key Research and Development Program grant 2018YFC1311500 (to Dr Z.-Y. Yuan).
Acknowledgment
The study is funded by National Natural Science Foundation of China grant 81941005 (to Dr Z.-Y. Yuan) and the National Key Research and Development Program grant 2018YFC1311500 (to Dr Z.-Y. Yuan). All authors have read this manuscript and approved it for publication.
Histopathologic characteristics of atherosclerotic coronary disease and implications of the findings for the invasive and noninvasive detection of vulnerable plaques.
Effect of atorvastatin therapy on fibrous cap thickness in coronary atherosclerotic plaque as assessed by optical coherence tomography: the EASY-FIT study.
Higgins JPT Green S Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (update March 2011). The Cochrane Collaboration,
2011 (Available at:)
Concomitant use of Rosuvastatin and Eicosapentaenoic acid significantly prevents native coronary atherosclerotic progression in patients with in-stent neoatherosclerosis.
Effects of the addition of eicosapentaenoic acid to strong statin therapy on inflammatory cytokines and coronary plaque components assessed by integrated backscatter intravascular ultrasound.
Effect of Eicosapentaenoic and Docosahexaenoic acids added to statin therapy on Coronary Artery plaque in patients with Coronary Artery disease: a Randomized Clinical Trial.
Effect of n-3 polyunsaturated fatty acids on regression of Coronary Atherosclerosis in statin treated patients undergoing percutaneous coronary intervention.
Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial.
Relationship between changes in coronary atherosclerotic plaque burden measured by intravascular ultrasound and cardiovascular disease outcomes: a systematic literature review.
Triglyceride- and cholesterol-rich lipoproteins have a differential effect on mild/moderate and severe lesion progression as assessed by quantitative coronary angiography in a controlled trial of lovastatin.
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