Habitual Use of Fish Oil Prevents CVD, Real-world Data Suggest

Routinely taking fish oil supplements rich in omega-3 fatty acids may help prevent cardiovascular disease and related mortality over the long term in people initially free of heart disease, new observational data suggest, adding to the ongoing debate about the role of fish oil supplements for primary prevention.

In the UK Biobank cohort, self-reported habitual use of fish oil supplements at baseline was associated with lower risks of incident CVD events and of all-cause and CVD mortality over a median follow-up of 8 to 9 years (adjusted HRs ranging from 0.84 to 0.93), according to researchers led by Zhi-Hao Li, PhD (Southern Medical University, Guangzhou, China).

“These findings indicate that habitual use of fish oils is associated with a marginal benefit for CVD events in the general population, supporting their use for the prevention of mortality from all causes and CVD,” Li et al write in their paper published online March 4, 2020, ahead of print in the BMJ. “Future studies are needed to examine the extent to which the dose of fish oil supplements influences the ability to achieve a clinically meaningful effect.”

The results appear at first glance to conflict with those of the VITAL trial, which failed to show that fish oil reduced major cardiovascular events or new cancer diagnoses in men and women free from cancer and CVD at baseline. There was a reduction in the secondary endpoint of MI, however, and exploratory analyses suggested lower risks of total coronary heart disease (CHD) and PCI.

Dariush Mozaffarian, MD, DrPH (Tufts Medical School, Boston, MA), said those secondary and exploratory endpoints in what was a null trial are important because decades of study has suggested that fish oil supplementation would reduce risk of CHD and not total CVD. “If that was a random finding, I would be less focused on it, but that’s exactly what we would have predicted based on the mechanistic studies,” he commented to TCTMD.

Based on VITAL, “if I were making guidelines, I would say that there is some evidence that fish oil could reduce coronary heart disease in primary prevention,” Mozaffarian said. “It’s not cut and dried. It’s not absolute. We need at least probably two more large definitive trials to make it cut and dried and absolute, but it’s certainly suggestive. And when you combine it with no evidence for harm and other studies like this one, observational studies, I think the overall body of evidence is supportive.”

Evidence Is Mixed

Although fish oil supplements have become popular based on observational studies supporting a benefit in terms of CVD risk reduction, some recent randomized trials have dampened enthusiasm. In addition to VITAL, ASCEND showed that omega-3 fatty acid supplementation failed to reduce serious vascular events in diabetic patients without established cardiovascular disease.

Recent meta-analyses of randomized trials have provided conflicting results. One published in 2018 before results from ASCEND, VITAL, and REDUCE-IT were released showed that omega-3 fatty acid supplementation was not associated with reduced risks of CHD, stroke, coronary revascularization, and any major vascular events in high-risk patients. A more recent meta-analysis published in 2019 that included those trials, in contrast, demonstrated that supplement use was tied to lower risks of MI, total CHD, death from CHD or CVD, and total CVD, even when REDUCE-IT—which showed significant benefits of a prescription omega-3 fatty acid formulation in patients with high triglycerides—was excluded.

We need at least probably two more large definitive trials to make it cut and dried and absolute, but it’s certainly suggestive. Dariush Mozaffarian

“Although randomized controlled trials generate the best evidence for the effects of interventions, their findings are difficult to generalize to large, more-inclusive populations because of their well-known limitations,” Li et al write. “Therefore, complementary information on the effectiveness of fish oil supplements is needed through evaluation in real-life settings of large-scale cohort studies.”

UK Biobank

To that end, they examined data from the UK Biobank, a population-based cohort of more than half a million people ages 40 to 69 from England, Scotland, and Wales. The current analysis included 427,678 people (mean age 56 years; 55% women) who did not have CVD or cancer at baseline and who had information on supplement use available. At baseline, 31.2% said they regularly took fish oil supplements. Patients were then followed for a median of 8.1 years for CVD events and 9.0 years for mortality.

On multivariable adjustment, habitual use of fish oil supplements was associated with lower risks of a variety of CVD-related outcomes, except for fatal stroke.

Long-term Outcomes Before and After Multivariable Adjustment

The relationship between use of fish oil and CVD event risk appeared stronger in patients with prevalent hypertension, whereas the associations with all-cause mortality risk seemed stronger for men and current smokers.

Discrepancy Between Studies

The investigators say that other studies that have not shown significant relationships between fish oil supplementation and CVD prevention could have suffered from insufficient sample sizes and numbers of outcome events.

In VITAL, for instance, they calculated the post hoc study power for major cardiovascular events to be only 0.78. They note, too, that the point estimate for a reduction in CVD events was similar in VITAL (HR 0.92) and this study (HR 0.93). “The confidence interval estimation (0.90 to 0.96) in our study suggests that omega-3 fatty acids have a significant association with CVD events,” Li et al write. “Therefore, we postulate a marginal inverse association between fish oil supplementation and CVD events.”

The researchers also say that dose may come into play, noting that the dose of omega-3 fatty acids was about 4.75-fold higher in REDUCE-IT, which met its primary endpoint, than in VITAL. Moreover, the 2019 meta-analysis indicating a benefit of fish oil also showed that higher doses would be more effective. “This finding indicates that the conflicting results from the randomized controlled trials could be due to sample sizes and the doses of fish oil supplements,” Li et al say.

They acknowledge that their own analysis has some limitations, including the lack of detailed information on dose, formulation, and duration of fish oil use; the potential for confounding or reverse causality; and the difficulty in separating the effects of a healthy lifestyle from those of fish oil supplementation.

Taking Fish Oil ‘Very Reasonable’

Commenting for TCTMD, JoAnn Manson, MD, DrPH (Brigham and Women’s Hospital and Harvard Medical School, Boston, MA), one of the chairs of the VITAL steering committee, said that “observational studies of supplement users and health outcomes need to be considered with caution because there are many potential confounding factors that come into play in terms of who chooses to take supplements and who chooses not to.” Thus, correlations in observational data do not prove causation.

That said, real-world data can be complementary to information from randomized clinical trials, especially when the two are reasonably well aligned, as is the case with studies looking at the impact of omega-3 fatty acid supplementation on coronary risk, Manson added.

“I think we have a good idea now of the effect of omega-3s on heart health,” she said. “There does seem to be a benefit for reducing risk of coronary disease.”

There is a need for additional studies, however, and both randomized and observational studies have a role to play, Manson said. In particular, additional trials looking at omega-3 fatty acid supplementation for primary prevention in high-risk patients are needed, with varying doses and formulations. But trials can be limited in their ability to look at long-term use, she added, highlighting the need for more observational research as well.

Mozaffarian also underscored the importance of observational research—with all of its inherent limitations—when examining the impact of interventions like fish oil supplementation on long-term disease risks.

“Trials and observational studies each have their own strengths and limitations, and of course animal experiments and other types of mechanistic studies have their own strengths and limitations,” he said. “I think there’s been an overreliance and an overemphasis on randomized controlled trials as the only standard and really we have to use all the evidence. So I think if you put all the evidence together—the evidence from VITAL, the evidence from REDUCE-IT, the evidence from ASCEND, the evidence from this study—it supports . . . that low-dose fish oil supplements probably have some cardiovascular benefit.”

If people want to improve their health, and indications are that eating omega-3 fatty acids is important, Mozaffarian said, “then my number one recommendation is still to do so by eating oily fish two or three times per week. But if people can’t eat oily fish two or three times per week for whatever reason . . . or if they do eat oily fish but still want to be sure they’re getting enough omega-3s, taking a daily nonprescription fish oil supplement is very reasonable.”