Does Fish Oil Reduce the Risk of Cardiovascular Events and Death? Recent Level 1 Evidence Says Yes

Abstract

Over the past decade there has been a considerable debate whether fish oil supplementation works to prevent and/or treat cardiovascular disease. This is due to the fact that previous studies testing fish oil in Italy and Japan found significant reductions in all-cause mortality, sudden cardiac death, and cardiovascular events, whereas more recent studies have in general been considered negative. We will discuss the reasons for these discrepancies and pave a better path forward when it comes to interpreting studies testing fish oil for the prevention or treatment of cardiovascular disease.

Introduction

Our group has previously published several academic articles explaining why earlier trials testing fish oil showed positive results, whereas more recent publications showed negative results.^{1, 2} There are several key reasons for this such as; 1) differences in study population (less benefit when testing primary prevention patients versus those with acute myocardial infarction or secondary prevention); 2) background omega-6 intake (less benefit in studies with a higher background omega-6 intake); 3) baseline omega-3 intake (less benefit with a higher baseline omega-3 intake); 4) concomitant medication use (less benefit in studies with greater use of statins, blood pressure medications, aspirin, etc.); and 5) omega-3 dosing (less benefit when using lower omega-3 doses).

When testing a population with a good baseline omega-3 intake, high baseline omega-6 intake, low baseline risk of cardiovascular disease, high concomitant use of cardiovascular medications and only small doses of omega-3s are used, it will be extremely difficult, if not impossible, to show benefits. Thus, before we blithely label study results as being “positive” or “negative,” we need to understand the nuances within each of the studies. At the very least, baseline omega-3 index should be measured, along with follow-up omega-3 index measurements every three months until trial end to ensure an appropriate omega-3 index of approximately 8% is reached and sustained throughout the trial. Unfortunately, almost all studies have failed to do such testing. Furthermore, in nearly every fish oil study tested to date, there has been a consistent, significant and profound reduction in the risk of cardiovascular death and/or myocardial infarction. Thus, while the primary endpoint (typically utilizing a non-standard composite endpoint that often includes “soft events” such as hospitalizations) may have missed statistical significance, important secondary endpoints are almost always significantly improved. So, whether a study is considered “positive” or “negative” is in reality up to the interpretation of the data by the clinician.

Considering the nuances when it comes to interpreting studies that test fish oil for the prevention or treatment of cardiovascular disease, we will now examine some of the more recent fish oil studies.

REDUCE-IT

The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) randomized a total of 8,179 patients with hypertriglyceridemia on statin therapy (71% for secondary prevention of cardiovascular events) at baseline to either 4 grams/day of Icosapent Ethyl or placebo.³ Those given Icosapent Ethyl had a significant 25% reduction in the primary endpoint (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina). There were also significant reductions in key secondary endpoints including a 26% reduction in major adverse cardiovascular events, a 20% reduction in cardiovascular death, and a 31% reduction in sudden cardiac death. REDUCE-IT dramatically showed that if you give a high enough dose of omega-3s, to a population that is primarily made up of secondary prevention patients, there can be significant benefits on numerous hard cardiovascular endpoints.

VITAL

The VITamin D and OmegaA-3 TriaL (VITAL) was a randomized controlled trial in 25,871 participants older than 50 years of age with no previous history of cancer or cardiovascular disease.⁴ The median follow-up was 5.3 years with fish oil given at 1 gram per day (460 mg EPA and 380 mg of DHA). There was no significant reduction in the primary endpoint (a composite of myocardial infarction, stroke or death from cardiovascular causes). However, there were significant reductions in myocardial infarction (28%) and coronary heart disease death (17%). Thus, while many consider VITAL a negative trial, there were important reductions in key secondary endpoints. Furthermore, in those consuming less than 1.5 fish meals per week, there was a highly significant reduction in the risk of major adverse cardiovascular events by 19%, and a 40% reduction in myocardial infarction. Therefore, if you eat more than 1.5 fish meals per week, you may not get a significant benefit with additional fish oil supplementation, which from a nutritional deficiency perspective makes complete sense. Clearly, the devil is in the details.

ASCEND

A Study of Cardiovascular Events iN Diabetes (ASCEND) was a seven-year randomized trial in 15,480 patients with diabetes without known cardiovascular disease who received 1-gram capsules of Lovaza compared to olive oil.⁵ There was no significant reduction in the primary endpoint (myocardial infarction, stroke or vascular death). However, there was a significant 18% reduction in vascular death (defined as death from coronary disease, stroke or other vascular causes). This important benefit was largely dismissed, and the trial was considered a failure. However, we believe this interpretation is unfair, especially considering the low dose of omega-3 employed in this study.

STRENGTH

The Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia (STRENGTH) was a double-blind, randomized, multicenter trial in 13,078 statin-treated participants who were given either 4 grams of omega-3s (a formulation of EPA and DHA as omega-3 carboxylic acids) or corn oil.⁶ There was no significant reduction on the primary endpoint with omega-3s. Despite this fact, there was a significant 15% reduction in coronary events in patients with established cardiovascular disease at baseline in those who received the omega-3s. This again confirms that omega-3s, in those with established cardiovascular disease, has consistent benefits for reducing coronary events.

OMEMI

The Omega-3 fatty acids in Elderly with Myocardial Infarction (OMEMI) study, was a multi-center, randomized clinical trial adding 1.8 grams of omega-3s (930 mg EPA and 660 mg DHA) versus corn oil daily to standard of care in 70–82 year-old patients with fairly recent (2–8 weeks) acute myocardial infarction.⁷ This study failed to show any benefits with omega-3s compared to corn oil. However, it is important to note that most deaths occur early on after a myocardial infarction and waiting 2–8 weeks to give omega-3s, as opposed to within hours of the acute event, may have prevented any benefit from being found, especially when this study testing omega-3s on top of current optimal background medical therapy.

Arrhythmias

There are some studies that have suggested that consuming fish oil may increase the risk of arrhythmias,^6,8 whereas other studies have found no increased risk⁹ and yet others reported a lower risk^10–16. The data are currently inconclusive on this. More importantly, none of these randomized trials found an increase in stroke, sudden cardiac death or all-cause mortality. To the contrary, both the REDUCE-IT and the Japan Eicosapentaenoic Acid Lipid Intervention Study (JELIS) trials found significant 20 to 30% reductions in stroke.¹⁷ Thus, it is uncertain what the true risk of arrhythmias (and its consequences) is with supplemental fish oil.

Recent Definitive Evidence

An expert meta-analysis or systematic review of collective information synthesized from individual, well-designed, randomized placebo-controlled trials is considered the highest level of evidence in modern medicine for determining the efficacy of a treatment.¹⁸ Benasconi and colleagues very recently performed such a meta-analysis, which comprised 42 studies (including the STRENGTH and OMEMI trials) with a combined 149,359 participants.¹⁹ The totality of this evidence regarding the cardiac effects of omega-3 supplementation shows statistically significant reductions in fatal myocardial infarction (35%), all myocardial infarctions (13%), and coronary heart disease mortality (9%) (Figure 1). These authors concluded that EPA and DHA intake is an effective lifestyle intervention for protection against cardiovascular disease.

Figure 1.

Pooled results from meta-analysis. The figure shows the pooled estimate of relative risk and 95% confidence interval, as well as the number of studies and combined number of participants. CHD, coronary heart disease; CVD, cardiovascular disease; MI, myocardial infarction.¹⁹

Conclusion

Most “negative” fish oil trials can actually be considered positive when looking at important secondary endpoints such as coronary heart disease death or myocardial infarction. Ultimately, the outcome of any trial testing fish oil will depend on the baseline characteristics of the population, the dose employed and the baseline intake of omega-3/omega-6 fatty acids.

Fish oil supplementation has decades worth of evidence including a recent pooled analysis of 17 prospective studies in 42,466 individuals showing that those with the highest circulating long-chain omega-3 levels have a 15–18% lower risk of death versus those in the lowest quintile (Figure 2).²⁰ Moreover, clinical studies testing fish oil over the past several decades have shown significant reductions in all-cause death, sudden cardiac death, coronary heart disease death and myocardial infarction, particularly in a secondary prevention population. This suggests, that for those who have already experienced a cardiovascular event, in particular a coronary heart disease event, that fish oil has an important role to play for preventing and treating recurrent events and coronary heart disease death.

Figure 2.

Associations of circulating long-chain n-3 PUFA levels with all-cause mortality: nonlinear dose-response meta-analysis in the Fatty Acids and Outcomes Research Consortium. HR and cohort-specific quantiles are presented in the vertical and horizontal axis, respectively.

The best estimates and their CI are presented as black lines and gray-shaded areas, respectively. The 10th percentile was selected as a reference level and the x-axis depicts 5th to 95th percentiles. Potential nonlinearity was identified for EPA (p = 0.0004) but not for the others (p > 0.05). All HRs are adjusted for age, sex, race, field center, BMI, education, occupation, marital status, smoking, physical activity, alcohol intake, prevalent diabetes, hypertension, and dyslipidemia, self-reported general health, and the sum of circulating n-6 PUFA (linoleic plus arachidonic acids).²⁰