No Cardiovascular Benefit With Omega-3 Fatty Acid Supplements: Meta-analysis

Omega-3 polyunsaturated fatty acid supplements do not provide any protection against cardiovascular disease events, according to the results of a large meta-analysis.

In nearly 78,000 high-risk individuals participating in ten clinical trials, the addition of omega-3 fatty acids did not reduce the risk of coronary heart disease, stroke, coronary revascularization, or any major vascular events, according to the researchers. Additionally, there was no benefit observed in any important subgroups, including people with prior coronary heart disease, diabetes, or elevated triglycerides.

The results published this week in JAMA Cardiology conflict with a 2017 American Heart Association (AHA) science advisory, where omega-3 fatty acids were given a lukewarm endorsement for secondary prevention of coronary heart disease and sudden cardiac death. In patients with prior heart disease, the AHA stated omega-3 polyunsaturated fatty acid supplementation was a “reasonable” consideration (class IIa recommendation).

Robert Clarke, MD (University of Oxford, England), who led the meta-analysis, told TCTMD that guideline writers make decisions based on the best available evidence. At the time, there was still some uncertainty about the benefit of omega-3 fatty acids given the conflicting results and different trial designs, he said.

“Medicine is constantly reevaluating the evidence base,” said Clarke. “Our conclusions do provide clarity, and while there are guidelines advocating benefit, our results provide no support for those recommendations to give omega-3 fatty acids for [reducing the risk of] fatal coronary heart disease or any other type of coronary disease.”

David Siscovick, MD (New York Academy of Medicine, New York, NY), the lead author of the AHA science advisory recommending omega-3 fatty acids, applauded the meta-analysis, telling TCTMD the results were not particularly surprising and have more in common with their report than not.

“To a large extent, the findings are similar, or least consistent, although there are differences, which are modest in terms of the findings,” he said. “I would say the main differences are how they interpret the data and what they think are the implications for clinicians.”

The bottom-line, said Siscovick, is that despite the lack of benefit observed in the meta-analysis, he would not alter any of the AHA recommendations. He is not disputing their findings, but instead pointing out the two groups had different goals when performing their reviews. The AHA’s aim was to provide clinical direction to practicing physicians. “Our advisory was really targeting clinical indications,” Siscovick said. “It was intended to inform physicians so that when they address these issues with patients, they’d know what’s known and what’s not known and would be in a position to make a reasonable recommendation.”

Omega-3 Treatment Trialists’ Collaboration

Over the years, there have been several meta-analyses attempting to address the question of benefit with omega-3 fatty acid supplementation. Two of those showed no beneficial effect, while a third suggested omega-3 fatty acids might reduce the risk of fatal coronary heart disease events. Clarke told TCTMD this latest meta-analysis differs in that investigators of the individual studies agreed to a join a collaboration and participated in the study.

“Our results provide no support for those recommendations to give omega-3 fatty acids for [reducing the risk of] fatal coronary heart disease or any other type of coronary disease.” Robert Clarke

The Omega-3 Treatment Trialists’ collaboration is based on aggregated study-level data obtained from the principal investigators of all 10 randomized clinical trials of omega-3 fatty acids. Importantly, the researchers adhered to a prespecified study protocol and outlined CVD subtypes and subgroups they wished to investigate.

Overall, the use of omega-3 fatty acids did not reduce the risk of nonfatal MI, coronary heart disease death (including sudden cardiac death and ventricular arrhythmias), any coronary heart disease, or major vascular events. The researchers observed no heterogeneity by dose or by subgroup, including patients with prior coronary heart disease. Even among individuals with triglycerides greater than 150 mg/dL, there was no evidence of benefit. Additionally, there was no benefit observed when they restricted their analysis to open-label or blinded studies. 

No matter where they looked, said Clarke, they didn’t turn up any advantage to using omega-3 fatty acids. “They are still widely used in the general population and what we’ve shown is that there was no evidence of harm, like mortality—people aren’t dying more or getting cancer—but it’s important people, as well as their doctors, are aware of the best available evidence,” he said.

The results also reinforce the importance of proven medical therapy, said Clarke, such as statins and blood pressure medications, when needed, as well as adhering to a heart-healthy lifestyle. That would include eating fish once or twice per week, he added.

Two Ways of Looking at Same Data

The AHA recommendations, written on behalf of the Nutrition Committee of the Council on Lifestyle and Cardiometabolic Health, were not based on a meta-analysis, but rather made by looking at the individual studies to assess the relative strengths and limitations. Siscovick noted that their definition of clinical events differed, specifically fatal coronary heart disease events, and that the purpose of their report was to help physicians make sense of accumulated data.  

The AHA report rules out omega-3 fatty acid supplements for primary prevention, as well as nearly all clinical conditions, the exception being use in the secondary prevention of heart failure (class IIa) and secondary prevention of coronary heart disease/sudden cardiac death.

Siscovick said that in both instances, the recommendation is “reasonable to consider,” which indicates there is still some uncertainty. However, given that there could be as much as a 10% reduction in the risk of fatal coronary disease events with omega-3 fatty acids, and no evidence of harm, they wanted to give physicians the option, said Siscovick.

He noted that in the meta-analysis by Clarke and colleagues, the reduction in coronary heart disease death is borderline significant (rate ratio 0.93; 99% CI 0.85-1.00). Additionally, the researchers do not tease out whether there might be a specific benefit in the reduction of sudden cardiac death, which accounts for a large proportion of the risk in patients with prior coronary heart disease. “It suggests there might be a 7% lower risk given their definition of coronary heart disease mortality, which was broader than ours,” said Siscovick.

Clarke and Siscovick both pointed out that other studies are ongoing, so the omega-3 fatty acid story is not yet over. One study, ASCEND, is assessing the benefit of omega-3 fatty acid supplementation for the primary prevention of CVD events in more than 15,000 people with diabetes. The VITAL study, which is even larger, is testing whether omega-3 fatty acids reduce the risk of CVD and stroke in 25,000 individuals without a history of heart disease.

“The fact that there’s 78,000 people in our analysis, we’d be really surprised if either the results of ASCEND or VITAL differed from what we observed,” said Clarke. “But by the end of 2018, we’ll have further randomized evidence on another 40,000 participants.”

In addition to ASCEND and VITAL, two trials investigating prescription-strength omega-3 fatty acid supplements are also underway. Those trials, REDUCE-IT and STRENGTH, are expected to be completed late this year and in 2019, respectively.