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Effects of Omega-3 fatty acid on major cardiovascular events and mortality in patients with coronary heart disease: A meta-analysis of randomized controlled trials
Corresponding author. Center of Translational Medicine, Nanjing University Medical School, 22 Hankou Road, Nanjing 210093, China. Tel./fax: +86 25 83595103.
Affiliations
Center for Translational Medicine, Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
There is considerable discrepancy regarding the protective effects of Omega-3 polyunsaturated fatty acids (Omega-3 PUFAs) in patients with coronary heart disease (CHD) from the early-phase clinical randomized controlled trials (RCTs). We conducted a meta-analysis of RCTs to address this issue.
Data synthesis
Pubmed, the Cochrane Central Register of Controlled Trials, and EMBASE databases (∼May 2013) were systematically searched. Odds ratios (OR) and associated 95% CI were retrieved by using random-effect model according to heterogeneity. A total of 14 RCTs involving 16,338 individuals in the Omega-3 PUFAs group and 16,318 in the control group were identified. Patients assigned to Omega-3 PUFAs did not demonstrate satisfactory improvements on major cardiovascular events (OR, 0.93; 95% CI, 0.86 to 1.01; P = 0.08; I2 = 46%). By contrast, the reduced risks of death from cardiac causes, sudden cardiac death and death from all causes (OR, 0.88; 95% CI, 0.80 to 0.96; P = 0.003; I2 = 0%; OR, 0.86; 95% CI, 0.76 to 0.98; P = 0.03; I2 = 29%; and OR, 0.92; 95% CI, 0.85 to 0.99; P = 0.02; I2 = 6%; respectively) were shown.
Conclusions
Supplement of Omega-3 PUFAs in patients with CHD is not associated with a protective effect on major cardiovascular events, while it does exert beneficial effects in reducing death from cardiac causes, sudden cardiac death and death from all causes. However, with currently available cardio-protective therapies, whether dietary supplementation with Omega-3 PUFAs should be still considered in patients with CHD is currently debated.
Intake of long chain Omega-3 polyunsaturated fatty acids (Omega-3 PUFAs) derived from marine sources, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) [
], is widely consumed as supplements within the community, and has been long recommended by health authorities to provide cardiovascular protection for the management of patients with coronary heart disease (CHD). For example, World Health Organization recommended an adequate intake of PUFAs in the range 6–10% of daily energy intake for patients with cardiovascular diseases (CVD) [
]. These recommendations were made on the basis of numerous large randomized controlled trials (RCTs) demonstrating that Omega-3 PUFAs supplementation leads to a marked reduction in cardiovascular events and mortality in diverse patient populations [
GISSI-Prevenzione Investigators Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico.
Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.
]. By contrast, some large RCTs reported no additional protection provided by Omega-3 PUFAs application over guideline-adjusted treatment in patients with myocardial infarction (MI) or at high risk for CVD [
OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction.
]. The conflicting findings reported added notable controversy to the common belief of Omega-3 PUFAs supplement in the management of CHD.
Given the inconsistency of prior trials assessing the potential impact of Omega-3 PUFAs on clinical outcomes, in the present study, we performed a meta-analysis of RCTs to analyze the effects of Omega-3 PUFAs in preventing major cardiovascular events and mortality compared with controls in patients with CHD.
Methods
Literature search and including criteria
Pubmed, the Cochrane Central Register of Controlled Trials, and EMBASE databases (from inception to May 2013) were systematically searched for relative RCTs. Search algorithm was “(Omega 3 OR PUFA OR fish oil OR marine oil OR cod liver oil OR n-3 fatty acid OR polyunsaturated fatty acid OR eicosapentaenoic acid OR docosahexaenoic acid OR EPA OR DHA) AND (cardiac death OR coronary heart disease OR heart disease OR myocardial infarction OR angina OR heart failure OR cardiovascular disease) AND (random*)” following database-appropriate terms. The reference lists and related links of retrieved articles were also examined for studies potentially eligible for inclusion.
Inclusion criteria were: a) prospective RCTs published in English; b) Omega-3 PUFAs or placebo orally administered through supplements for patients with ischemic CHD (including established atherosclerosis in native coronary arteries, angina, CAD, MI and ischemic heart failure (HF)); c) Omega-3 PUFAs dosing duration >4 weeks; and d) reporting safety or cardiovascular events during follow-up. Although plant-derived α-linolenic acid (ALA) can be enzymatically converted to EPA and DHA in human, the process is inefficient (as low as 0.04%–2.84%) [
Effect of altered dietary n-3 fatty acid intake upon plasma lipid fatty acid composition, conversion of [13C]alpha-linolenic acid to longer-chain fatty acids and partitioning towards beta-oxidation in older men.
]. As a result, trials using ALA was excluded. Studies using diet supplements of fish were excluded, too. Studies pertained to patients with other cardiovascular diseases such as stroke, arrhythmias and non-ischemic heart failure were excluded. When there were several reports conducting the same patients' population at different follow-up periods, the longest follow-up was retained.
Data extraction and quality assessment
Study selection, data extraction, and quality assessment were completed in duplicate and independently by two reviewers (Y. W. and J. D.) by using a standardized protocol. In the case of disagreement, a third reviewer independently assessed the data for consensus. Serious cardiovascular events (such as cardiac death, recurrent myocardial infarction, additional coronary revascularization procedures, and stroke) and neoplasm during follow-up were collected. Methodological quality of the included studies and the risk of bias conferred were evaluated.
Statistical analysis
All data were analyzed by using RevMan software version 5 (Cochrane Collaboration, 2011) and Stata software version 12.0 (Stata Corporation, College Station, TX). The primary outcomes examined were major cardiovascular events (comprising fatal and nonfatal cardiovascular events and the cardiac interventions percutaneous coronary intervention and coronary-artery bypass grafting). The secondary outcomes were all cause mortality, sudden cardiac death and death from cardiac causes. As dichotomous results, Odds ratios (OR) and their associated 95% confidence interval (CI) were retrieved. The extent of the observed heterogeneity was explored by using I2 (a value of 0% indicates limited heterogeneity, and larger values demonstrate increasing heterogeneity). A random-effect model was chosen for analysis in the case of significant heterogeneity among trials (I2 ≥ 50%, P < 0.1) [
]. Planned subgroup analyses according to the severity of CHD (MI vs. coronary atherosclerosis), Omega-3 PUFAs dosage (≤1 g/d vs. > 1 g/d) and duration (<2 y vs. > 2 y) were conducted for treatment subgroup interactions by using random-effect model. The sensitivity analysis was done by excluding one trial at a time. The presence of publication bias was assessed by visual examination of Funnel plots of the primary outcome and quantified by the Begg's and Egger's Tests (on outcomes which were reported in over 9 RCTs). P values equal or less than 0.05 were considered to be statistically significant.
Results
Study characteristics and quality assessment
The flow diagram of article selection was shown in Fig. 1. 14 RCTs [
GISSI-Prevenzione Investigators Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico.
Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.
OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction.
An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia.
Effects of polyunsaturated omega-3 fatty acids on responsiveness to dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: the OMEGA-PCI (OMEGA-3 fatty acids after pci to modify responsiveness to dual antiplatelet therapy) study.
Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol.
Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival–4.
] were included in the meta-analysis, comprising a total of 16,338 individuals in the Omega-3 PUFAs group and 16,318 in the placebo one (Supplementary Table 1). Patients treated in these RCTs had CHD such as CAD, AMI, post-MI and heart failure, etc. 2 of these 14 studies supplied the Omega-3 PUFAs or placebo for less than 3 months [
Effects of polyunsaturated omega-3 fatty acids on responsiveness to dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: the OMEGA-PCI (OMEGA-3 fatty acids after pci to modify responsiveness to dual antiplatelet therapy) study.
An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia.
GISSI-Prevenzione Investigators Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico.
Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.
OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction.
Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol.
Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival–4.
]. The comparison arms of the included trials got regular medical therapy with/without placebos such as corn oil, soybean oil, olive oil, oleic acid and aluminum hydroxide, etc. Notably, there were RCTs with relatively small sample sizes (range, 59–551 patients) [
An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia.
Effects of polyunsaturated omega-3 fatty acids on responsiveness to dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: the OMEGA-PCI (OMEGA-3 fatty acids after pci to modify responsiveness to dual antiplatelet therapy) study.
Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol.
Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival–4.
GISSI-Prevenzione Investigators Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico.
Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.
OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction.
GISSI-Prevenzione Investigators Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico.
GISSI-Prevenzione Investigators Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico.
] compared Omega-3 PUFAs and/or Vitamin E with placebo. To be included in the analysis, these 2 RCTs were stratified into arms with/without Omega-3 PUFAs as the original RCTs did in their results.
The methodological quality of the RCTs included was described in Supplementary Table 2. All the 14 RCTs randomized their participants, but only 9 described an adequate method of generating randomized sequences, and 6 of them failed to describe allocation concealment. All the 14 trials blinded outcome assessors and reported details of withdrawn patients.
Effect of Omega-3 PUFAs supplement on major cardiovascular events and deaths
Compared with controls, patients assigned to Omega-3 PUFAs demonstrated a trend of improvements on major cardiovascular events during follow-up, but without statistical significance (OR, 0.93; 95% CI, 0.86 to 1.01; P = 0.08; I2 = 46%) (Fig. 2A). Overall, compared with placebo, Omega-3 PUFAs supplementation significantly associated with reduced risks of death from cardiac causes (OR, 0.88; 95% CI, 0.80 to 0.96; P = 0.003; I2 = 0%), reduced sudden cardiac death (OR, 0.86; 95% CI, 0.76 to 0.98; P = 0.03; I2 = 29%), and reduced death from all causes (OR, 0.92; 95% CI, 0.85 to 0.99; P = 0.02; I2 = 6%) (Fig. 2B–D).
Figure 2Forest plot of odds ratio (OR), with 95% confidence interval (CI) on (A) major cardiovascular events; (B) death from cardiac causes; (C) sudden cardiac death; and (D) death from all causes in patients with coronary heart disease treated with Omega-3 polyunsaturated fatty acids compared with controls.
Among these major cardiovascular events occurred in those trials during follow-up, Omega-3 PUFAs supplementation significantly reduced the incidence of MI (OR, 0.85; 95% CI, 0.73 to 1.00; P = 0.04; I2 = 13%), but had no effects on the incidence of revascularization (OR, 0.91; 95% CI, 0.81 to 1.02; P = 0.11; I2 = 0%), unstable angina (OR, 0.63; 95% CI, 0.36 to 1.11; P = 0.11; I2 = 71%) and stroke (OR, 1.21; 95% CI, 0.99 to 1.47; P = 0.07; I2 = 0%) (Fig. 3A–D). When including the 4 trials [
GISSI-Prevenzione Investigators Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico.
Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.
OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction.
] reporting neoplasm, there was no obvious evidence that Omega-3 PUFAs supplement increased the risk of tumorigenesis (OR, 1.05; 95% CI, 0.89 to 1.25; P = 0.55; I2 = 28%) (Fig. 3E).
Figure 3Forest plot of Odds Ratio with 95% confidence interval (CI) in (A) myocardial infarction, (B) revascularization, (C) unstable angina, (D) stroke, and (E) neoplasm in patients with coronary heart disease treated with Omega-3 polyunsaturated fatty acids compared with controls.
To evaluate the influence of CHD severity on the effects of Omega-3 PUFAs supplement, trials were firstly divided into two subgroups according to clinical scenario: comparisons that treated patients with coronary atherosclerosis and comparisons that did those with MI (Table 1). And then the efficacy of Omega-3 PUFAs supplement on incidence of major cardiovascular events in CHD patients was then discussed with Omega-3 PUFAs given in different dosage (≤1 g/d vs. >1 g/d) and duration (<2 years vs. >2 years) (Table 1). Test of interaction showed significance for the subgroup differences according to clinical scenario (P = 0.05) and Omega-3 PUFAs' dosage (P = 0.03), but not significant according to duration of Omega-3 PUFAs' usage (P = 0.74).
Table 1Subgroup analysis examining the impact of Omega-3 PUFAs supplement on the incidence of major cardiovascular events compared with controls.
Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.
OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction.
Effects of polyunsaturated omega-3 fatty acids on responsiveness to dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: the OMEGA-PCI (OMEGA-3 fatty acids after pci to modify responsiveness to dual antiplatelet therapy) study.
Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol.
Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival–4.
OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction.
Effects of polyunsaturated omega-3 fatty acids on responsiveness to dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: the OMEGA-PCI (OMEGA-3 fatty acids after pci to modify responsiveness to dual antiplatelet therapy) study.
Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival–4.
GISSI-Prevenzione Investigators Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico.
Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol.
GISSI-Prevenzione Investigators Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico.
OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction.
Effects of polyunsaturated omega-3 fatty acids on responsiveness to dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: the OMEGA-PCI (OMEGA-3 fatty acids after pci to modify responsiveness to dual antiplatelet therapy) study.
Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol.
Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival–4.
In separate analysis, the incidence of major cardiovascular events was reduced in patients with coronary atherosclerosis after Omega-3 PUFAs supplement (OR, 0.49; 95% CI, 0.25 to 0.96; P = 0.04; I2 = 0%), while it was not statistically reduced in those with MI (OR, 0.98; 95% CI, 0.84 to 1.15; P = 0.85; I2 = 55%) (Table 1). We extracted data with higher Omega-3 dosage (>1 g/d), which showed a significantly reduced incidence of major cardiovascular events (OR, 0.78; 95% CI, 0.65 to 0.93; P = 0.006; I2 = 0%). Meta-analysis of the trials applying lower Omega-3 dosage (≤1 g/d) did not substantially change this estimate (1.01, 0.86–1.20) (Table 1). The benefits of Omega-3 supplementation were similar in patients who got less or more than 2 years treatment, although the incidence of major cardiovascular events was reduced in the latter, although did not reach statistical significance (Table 1).
Sensitivity analysis and publication bias
By excluding one trial at a time and computing meta-analysis estimates for the remaining studies, it showed that exclusion of the Alpha Omega Trial [
OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction.
] led to the statistical reduction of major cardiovascular events, suggesting the high weight of these studies. After visual inspections of funnel plots of major cardiovascular events (the primary outcome), there was no obvious evidence to suggest the presentence of publication bias (Supplementary Fig. 1). Both the Begg's and Egger's Tests of the outcomes such as major cardiovascular events (the primary outcome), death from cardiac causes, all death and MI, also showed no publication bias among the analyzed studies (Supplementary Table 3).
Discussion
The biological effects of Omega-3 PUFAs in CHD and its complications are wide ranging, including effects on lipids, blood pressure, cardiac and vascular function, prostanoids, concoagulation and immunological responses [
]. The recent published meta-analysis on Omega-3 PUFAs mainly included populations with cardiovascular risk factors or atherosclerotic vascular disease, instead of documental CHD. In a meta-analysis implemented in primary or secondary CVD prevention settings [
], Omega-3 PUFAs supplementation was not associated with a lower risk of all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke based on relative and absolute measures of association. When including a diverse group of populations with CAD, AMI, implantable cardiac defibrillation (ICD), and hypercholesterolaemia [
], supplement with Omega-3 PUFAs was associated with a significant reduction in deaths from cardiac causes but had no effect on arrhythmias or all cause mortality. In two meta-analyses [
Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials.
] of patients with CVD including CHD, lower limb atherosclerosis, ICD, stroke and hypercholesterolaemia, there was discrepancy on the protective effect of Omega-3 PUFAs. However, all these previous meta-analysis targeted on either populations with cardiovascular risk factors or patients with all kinds of atherosclerotic vascular disease. These combined types of participants or condition may result in potential statistical heterogeneity. In this study, we have limited our analysis to documental CHD and have evaluated the importance of early usage of Omega-3 PUFAs at the stage of coronary atherosclerosis, before MI and HF, on the risk of major cardiovascular events.
An impressive feature indicated by our meta-analysis is that Omega-3 PUFAs supplements in patients with CHD is associated with a significant reduction of the risks of death from cardiac causes, sudden cardiac death and death from all causes. Although there is insufficient evidence of a preventive effect of Omega-3 PUFAs supplements against major cardiovascular events in patients with CHD, subgroup analysis demonstrates a reduced incidence of major cardiovascular events in the setting of coronary atherosclerosis. This underlines the fact that Omega-3 PUFAs supplements should primarily focus on patients with less severe CHD such as coronary atherosclerosis; however, cautions in interpretation are required because of the small sample size in the 4 RCTs conducting this patients' population [
]. It seemed Omega-3 PUFAs had no effects on the incidence of unstable angina and stroke; but this conclusion was based on the limited trials included (4 RCTs reporting unstable angina and 2 reporting stroke). A more robust outcome should be incorporated in future trials with larger sample size.
In our study, it showed that exclusion of the Alpha Omega Trial [
OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction.
] led to the statistical reduction of major cardiovascular events when computing meta-analysis estimates for the remaining studies. For the Alpha Omega Trial [
], on one hand, it enrolled patients with diagnosed MI of median 3.7 y. During this period, the patients received sustained anti-MI therapy. On the other hand, it should be pointed out that the patients in this trial only took approximately 400 mg of EPA–DHA every day, which was the lowest dosage of Omega-3 PUFAs supplement among the 14 RCTs enrolled in our meta-analysis. For the Omega Trial [
OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction.
], the patients with AMI received considerably improved guideline-adjusted therapy compared to the previous ones. These characters of the single trial may be important for several reasons. Firstly, the discrepancy among the findings of the Alpha Omega Trial, the Omega Trial and the previous ones may be comprehensible, which is in consistent with the hypothesis that Omega-3 PUFAs may not have large benefits in patients receiving modern medical and interventional therapies [
]. In this circumstance, with contemporary cardioprotective therapies, whether Omega-3 PUFAs supplementation is still worthy recommendation to further improve CHD prognosis is debatable. Secondly, dosage and supplement duration are also an important determinant of patient outcome. Higher doses of Omega-3 PUFAs (for example, 2–4 g EPA + DHA/day) provide cardiovascular benefit on longer treatment duration [
]. Our subgroup analysis also provided evidence of a more significant reduction of major cardiovascular events in patients who got >1 g/d Omega-3 PUFAs; while longer supplementary duration (>2 years) did not show a more pronounced benefit than a shorter one (<2 years). It is conceivable that, patients with less severe CHD such as coronary atherosclerosis might especially profit from therapy with higher Omega-3 PUFAs' dosage. On the basis of the above considerations, further large RCTs with protocols integrate lessons learned from the first wave of trials are warranted.
Omega-3 PUFAs supplement is relatively safe in the 14 RCTs included. Miscellaneous adverse events were found during follow-up, mostly mild gastrointestinal discomfort, prolonged bleeding, diarrhea or nausea, infections and allergic reaction. Their frequency did not differ significantly between groups. The OMEGA trial reported slightly higher incidence of neoplasm in the treatment group [
OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction.
]. However, as to the Omega-3 PUFAs, there are even indications that it may protect against a range of cancer types such as prostate cancer and colorectal cancer [
GISSI-Prevenzione Investigators Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico.
Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.
OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction.
] reporting neoplasm did not support the tumorigenesis potential of the Omega-3 PUFAs. However, based on the limited RCTs focusing on neoplasm, special attentions on long-term safety are still warranted in the future epidemiologic studies.
In conclusion, our meta-analysis indicates that supplement of Omega-3 PUFAs in patients with CHD is not associated with a protective effect on major cardiovascular events, probably due to the improved cardio-protective treatment. However, Omega-3 PUFAs exert beneficial effects in reducing death from cardiac causes, sudden cardiac death and death from all causes. Several issues remain to be elucidated in further studies. First, the optimal dosage of Omega-3 PUFAs, the ratios of DHA to EPA and the supplement duration is yet to be determined. Second, whether coronary atherosclerosis, MI, or even HF is the target of Omega-3 PUFAs is still under discussion. Last but not least, when receiving contemporary cardio-protective therapies, are Omega-3 PUFAs still worthy recommendation for patients with CHD? The final word is being waiting.
Fundings
This work was supported by the National Natural Science Foundation of China (81100386, 81030013), the New Teachers' Fund for Doctor Stations, Ministry of Education of China (20110091120031), and the National Ministry of Science and Technology (2009CB918704).
Competing interests
The authors state no conflict of interest.
Appendix A. Supplementary data
The following are the supplementary data related to this article:
Supplementary Figure 1. Funnel plot for assessment of publication bias for major cardiovascular events in 11 included trials reporting data on this outcome.
Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico.
Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.
OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction.
Effect of altered dietary n-3 fatty acid intake upon plasma lipid fatty acid composition, conversion of [13C]alpha-linolenic acid to longer-chain fatty acids and partitioning towards beta-oxidation in older men.
An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia.
Effects of polyunsaturated omega-3 fatty acids on responsiveness to dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: the OMEGA-PCI (OMEGA-3 fatty acids after pci to modify responsiveness to dual antiplatelet therapy) study.
Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol.
Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival–4.
Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials.
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