Omega‐3 fatty acids for the primary and secondary prevention of cardiovascular disease New search for studies and content updated (conclusions changed)

Abstract

Abstract Background

Omega‐3 polyunsaturated fatty acids from oily fish (long‐chain omega‐3 (LCn3)), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)), as well as from plants (alpha‐linolenic acid (ALA)) may benefit cardiovascular health. Guidelines recommend increasing omega‐3‐rich foods, and sometimes supplementation, but recent trials have not confirmed this.

Objectives

To assess the effects of increased intake of fish‐ and plant‐based omega‐3 fats for all‐cause mortality, cardiovascular events, adiposity and lipids.

Search methods

We searched CENTRAL, MEDLINE and Embase to February 2019, plus ClinicalTrials.gov and World Health Organization International Clinical Trials Registry to August 2019, with no language restrictions. We handsearched systematic review references and bibliographies and contacted trial authors.

Selection criteria

We included randomised controlled trials (RCTs) that lasted at least 12 months and compared supplementation or advice to increase LCn3 or ALA intake, or both, versus usual or lower intake.

Data collection and analysis

Two review authors independently assessed trials for inclusion, extracted data and assessed validity. We performed separate random‐effects meta‐analysis for ALA and LCn3 interventions, and assessed dose‐response relationships through meta‐regression.

Main results

We included 86 RCTs (162,796 participants) in this review update and found that 28 were at low summary risk of bias. Trials were of 12 to 88 months' duration and included adults at varying cardiovascular risk, mainly in high‐income countries. Most trials assessed LCn3 supplementation with capsules, but some used LCn3‐ or ALA‐rich or enriched foods or dietary advice compared to placebo or usual diet. LCn3 doses ranged from 0.5 g a day to more than 5 g a day (19 RCTs gave at least 3 g LCn3 daily).

Meta‐analysis and sensitivity analyses suggested little or no effect of increasing LCn3 on all‐cause mortality (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.93 to 1.01; 143,693 participants; 11,297 deaths in 45 RCTs; high‐certainty evidence), cardiovascular mortality (RR 0.92, 95% CI 0.86 to 0.99; 117,837 participants; 5658 deaths in 29 RCTs; moderate‐certainty evidence), cardiovascular events (RR 0.96, 95% CI 0.92 to 1.01; 140,482 participants; 17,619 people experienced events in 43 RCTs; high‐certainty evidence), stroke (RR 1.02, 95% CI 0.94 to 1.12; 138,888 participants; 2850 strokes in 31 RCTs; moderate‐certainty evidence) or arrhythmia (RR 0.99, 95% CI 0.92 to 1.06; 77,990 participants; 4586 people experienced arrhythmia in 30 RCTs; low‐certainty evidence). Increasing LCn3 may slightly reduce coronary heart disease mortality (number needed to treat for an additional beneficial outcome (NNTB) 334, RR 0.90, 95% CI 0.81 to 1.00; 127,378 participants; 3598 coronary heart disease deaths in 24 RCTs, low‐certainty evidence) and coronary heart disease events (NNTB 167, RR 0.91, 95% CI 0.85 to 0.97; 134,116 participants; 8791 people experienced coronary heart disease events in 32 RCTs, low‐certainty evidence). Overall, effects did not differ by trial duration or LCn3 dose in pre‐planned subgrouping or meta‐regression. There is little evidence of effects of eating fish.

Increasing ALA intake probably makes little or no difference to all‐cause mortality (RR 1.01, 95% CI 0.84 to 1.20; 19,327 participants; 459 deaths in 5 RCTs, moderate‐certainty evidence),cardiovascular mortality (RR 0.96, 95% CI 0.74 to 1.25; 18,619 participants; 219 cardiovascular deaths in 4 RCTs; moderate‐certainty evidence), coronary heart disease mortality (RR 0.95, 95% CI 0.72 to 1.26; 18,353 participants; 193 coronary heart disease deaths in 3 RCTs; moderate‐certainty evidence) and coronary heart disease events (RR 1.00, 95% CI 0.82 to 1.22; 19,061 participants; 397 coronary heart disease events in 4 RCTs; low‐certainty evidence). However, increased ALA may slightly reduce risk of cardiovascular disease events (NNTB 500, RR 0.95, 95% CI 0.83 to 1.07; but RR 0.91, 95% CI 0.79 to 1.04 in RCTs at low summary risk of bias; 19,327 participants; 884 cardiovascular disease events in 5 RCTs; low‐certainty evidence), and probably slightly reduces risk of arrhythmia (NNTB 91, RR 0.73, 95% CI 0.55 to 0.97; 4912 participants; 173 events in 2 RCTs; moderate‐certainty evidence). Effects on stroke are unclear.

Increasing LCn3 and ALA had little or no effect on serious adverse events, adiposity, lipids and blood pressure, except increasing LCn3 reduced triglycerides by ˜15% in a dose‐dependent way (high‐certainty evidence).

Authors' conclusions

This is the most extensive systematic assessment of effects of omega‐3 fats on cardiovascular health to date. Moderate‐ and low‐certainty evidence suggests that increasing LCn3 slightly reduces risk of coronary heart disease mortality and events, and reduces serum triglycerides (evidence mainly from supplement trials). Increasing ALA slightly reduces risk of cardiovascular events and arrhythmia.

Author(s)

Asmaa S Abdelhamid, Tracey J Brown, Julii S Brainard, Priti Biswas, Gabrielle C Thorpe, Helen J Moore, Katherine HO Deane, Carolyn D Summerbell, Helen V Worthington, Fujian Song, Lee Hooper

Abstract

Plain language summary

Omega‐3 intake for cardiovascular disease

Review question

We reviewed randomised trials (where participants have an equal chance of being assigned to either treatment) examining effects of increasing fish‐ and plant‐based omega‐3 fats on heart and circulatory disease (called cardiovascular diseases, which include heart attacks and stroke), fatness and blood fats (lipids, including cholesterol, triglycerides, high‐density lipoprotein (HDL – 'good' cholesterol) and low‐density lipoprotein (LDL – 'bad' cholesterol)).

Background

The main types of omega‐3 fats are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both found in fish, and alpha‐linolenic acid (ALA) found in plant foods. Many people believe that taking omega‐3 supplements reduces risk of heart disease, stroke and death.

Trial characteristics

The evidence is current to February 2019. The review included 86 trials involving 162,796 people. These trials assessed effects of greater omega‐3 intake versus lower omega‐3 intake for at least a year on heart and circulatory disease. Twenty‐eight trials were very trustworthy (well‐designed so as not to give biased results). Participants were adults, some with existing illness and some healthy, living in North America, Europe, Australia and Asia. Most EPA and DHA trials provided capsules, few gave oily fish.

Key results

Increasing EPA and DHA has little or no effect on deaths and cardiovascular events (high‐certainty evidence) and probably makes little or no difference to cardiovascular death, stroke, or heart irregularities (moderate‐certainty evidence). However, increasing EPA and DHA may slightly reduce risk of coronary death and coronary events (low‐certainty evidence, coronary events are illnesses of arteries supplying the heart). To prevent one person having a coronary event, 167 people would need to increase their EPA and DHA, and 334 people would need to increase their EPA and DHA to prevent one person dying from coronary disease. EPA and DHA reduce triglycerides by about 15% but do not affect fatness or other lipids (high‐certainty evidence).

Eating more ALA (for example, by increasing walnuts or enriched margarine) probably makes little or no difference to all‐cause, cardiovascular or coronary deaths or coronary events but probably slightly reduces cardiovascular events and heart irregularities (moderate‐ or low‐certainty evidence). To prevent one person having a coronary event, 500 people would need to increase their ALA, 91 people to prevent one person having arrhythmia.

There is little evidence of effects of eating fish. EPA and DHA reduce triglycerides. EPA, DHA and ALA may be slightly protective of some heart and circulatory diseases.

Author(s)

Asmaa S Abdelhamid, Tracey J Brown, Julii S Brainard, Priti Biswas, Gabrielle C Thorpe, Helen J Moore, Katherine HO Deane, Carolyn D Summerbell, Helen V Worthington, Fujian Song, Lee Hooper

Reviewer's Conclusions

Authors' conclusions

Implications for practice

We found high‐certainty evidence that long‐chain omega‐3 fats (LCn3) do not have important positive or negative effects on mortality or cardiovascular events and moderate‐certainty evidence that they have little or no effect on cardiovascular disease mortality, stroke or arrhythmia in primary or secondary prevention. However, we found low‐certainty evidence that LCn3 slightly reduces risk of coronary heart disease mortality (number needed to treat for an additional beneficial outcome (NNTB) 334, NNTB 200 in secondary prevention, NNTB 1000 in primary prevention), and coronary heart disease events (NNTB 167, NNTB 143 in secondary prevention, NNTB 200 in primary prevention). As these effects are very small (and numbers needed to treat for an additional benefit high), supplemental LCn3 fats are probably not useful for preventing or treating cardiovascular disease. LCn3 fats can help to reduce serum triglycerides, though they do not appear to affect body fatness or other lipid fractions.

An NNTB of 167 means that 167 people will need to take LCn3 supplements for around four years each so that one of those people avoids a coronary heart disease event. The other 166 people receive no benefit. Similarly, an NNTB of 334 means that 334 people need to take LCn3 supplements for around four years each for one person to avoid death from coronary heart disease, the other 333 people do not benefit.

How does an NNTB of 143 or 500 compare with effective medications in cardiovascular disease prevention? Could we compare, for example, with the use of statins in secondary prevention of myocardial infarction or ezetimibe added to statins after acute coronary syndrome? In the 4S trial (Scandinavian Simvastatin Survival Study Group 1994), 8% of the participants taking simvastatin died, and 12% of those taking the placebo died, a difference of 4%, so the NNTB was 25. Twenty‐five people needed to take simvastatin for around five years to prevent one person dying. Most of us decide to take statins post‐myocardial infarction. Ten‐year NNTBs for statins in primary prevention when used according to appropriate guidance are around 30, to prevent one case of atherosclerotic cardiovascular disease (Mortensen 2019). The IMPROVE‐IT trial showed that giving ezetimibe in addition to statin to 50 people with acute coronary syndrome for seven years each prevents one person from having a cardiovascular event (Turgeon 2015).

Individuals may make differing decisions about whether an NNTB of 143 is useful. Perhaps NNTBs should be noted on fish oil supplement packages: “If 143 people with existing cardiovascular disease take this supplement for 5 years each then one of those 143 people will avoid a coronary event (such as a heart attack). If 1000 people without existing cardiovascular disease take this supplement for 5 years each then one person will avoid dying from coronary heart disease”. Then each of us could decide whether this is the way we wish to spend our money, on omega‐3 supplements or a different cardiovascular treat such as a pair of running shoes, healthy fruit or fish, or a relaxation class.

Most evidence on LCn3 fats came from trials of capsules of fish oil or eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) mixtures. While we did not see important differences between trials of supplemental capsules and trials of oily fish, there were few trials of oily fish. Fish and seafood are nutrient‐dense and rich in a variety of other nutrients (such as vitamin D, calcium, iodine, selenium) so are useful foods even without cardiovascular benefits. In light of the evidence in this review it would be appropriate to review official recommendations supporting supplemental LCn3 fatty acid intake.

We found low‐certainty evidence that increasing ALA may slightly reduce risk of cardiovascular disease events (NNTB 500) and moderate‐certainty evidence that increasing ALA probably reduces risk of arrhythmia (NNTB 91). However, there is probably little or no effect on all‐cause or cardiovascular mortality, coronary heart disease mortality or coronary heart disease events (low‐ and moderate‐certainty evidence). As with LCn3, effects of ALA were very small; 91 people would need to increase their ALA intake to prevent one person developing arrhythmia, and 500 would need to take more ALA to prevent one person experiencing a cardiovascular disease event. We found no evidence that ALA affected adiposity or serum lipids. Trials of ALA gave ALA‐rich or enriched foods such as walnuts or ALA‐enriched margarine.

Implications for research

There are several large ongoing trials of supplemental LCn3 fats (see Characteristics of ongoing studies, and large parts of VITAL 2019 are ongoing). We suggest that given the minimal protective effects suggested for omega‐3 fats in the large number of trials to date, no further trials should be initiated until the ongoing trials have reported. Ongoing and completed trials should make data on baseline LCn3 intake, and details of deaths, cardiovascular outcomes, lipids, adiposity and blood pressure available, as well as other key health outcomes, regardless of their primary outcomes.

Further large and high‐certainty trials of ALA carried out in lower‐ and higher‐income countries, and that assess baseline ALA intake and use biomarkers to assess compliance would be helpful to clarify the cardiovascular effects of ALA. Similarly trials of dietary fish would be helpful.

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