Table 3.

Meta-analyses published up to 2018 of RCTs investigating the effect of marine n-3 fatty acids on cardiovascular outcomes.

Study	Study Design	Form & Dosage of Marine-3 Fatty Acids	Duration of Treatment with Marine n-3 Fatty Acids	Pooled Effects of Marine n-3 Fatty Acids Versus Placebo
Bucher et al., 2002 [60]	11 RCTs (up to August 1999) representing 15,806 patients with CHD	Dietary (2 RCTs) and supplemental (9 RCTs) marine n-3 fatty acids with a dose range of 0.3–6.0 g/d EPA and 0.6–3.7 g/d DHA	6–46 months (mean: 20 months)	30% reduction in fatal MI
				30% reduction in sudden death
				20% reduction in overall mortality
Studer et al., 2005 [61]	14 RCTs (up to June 2003) representing 20,260 participants in primary and secondary prevention settings	Supplemental marine n-3 fatty acids; dose range not given	Mean: 1.9 ± 1.2 years	23% reduction in overall mortality
				32% reduction in cardiovascular mortality
Zhao et al., 2009 [62]	8 RCTs (up to June 2008) representing 20,997 patients with CHD	Dietary (3 RCTs) and supplemental (5 RCTs) marine	9–108 months (mean: 33 months)	57% reduction in sudden death in patients with prior MI
				39% increased risk of sudden death in patients with angina
		n-3 fatty acids with a dose range of 0.3–4.1 g/d EPA and 0.4–2.8 g/d DHA		29% reduction in cardiac death (NS)
				23% reduction in all-cause mortality (NS)
Marik and Varon, 2009 [63]	11 RCTs (up to December 2008) representing 39,044 patients with all stages of CVD including high-risk and low-risk subjects	Supplemental marine n-3 fatty acids with a dose range of 0.7–4.8 g/d EPA + DHA (mean: 1.8 ± 1.2 g/d)	1–4.6 years (mean: 2.2 ± 1.2 years)	13% reduction in cardiovascular death in high-risk patients
				13% reduction in sudden cardiac death in high-risk patients
				8% reduction in all-cause mortality in high-risk patients
				8% reduction in non-fatal cardiovascular events in moderate-risk patients.
Kotwal et al., 2012 [71]	20 RCTs (up to March 2011) representing 62,851 patients in primary and secondary prevention settings	Diet (3 RCTs) and supplemental (17 RCTs) marine n-3 fatty acids with a dose range of 0.8–3.4 g/d EPA + DHA	6 months–6 years	14% reduction in vascular death
				No effect on cardiovascular events, total mortality, coronary events, arrhythmia or cerebrovascular events
Kwak et al., 2012 [72]	14 RCTs (up to April 2011) representing 20,485 patients with CVD	Supplemental marine n-3 fatty acids with a dose range of 0.4–4.8 g/d EPA + DHA (mean: 1.7 g/d EPA + DHA)	1–4.7 years (mean: 2 years)	9% reduction in cardiovascular death
				No effect on cardiovascular events, all-cause mortality, sudden cardiac death, MI, congestive heart failure or stroke
Trikalinos et al., 2012 [73]	18 RCTs (up to May 2011) representing 51,264 patients	Supplemental marine n-3 fatty acids with a dose range of 0.27–6.0 g/d EPA + DHA	1–5 years	11% reduction in cardiovascular mortality
Rizos et al., 2012 [74]	20 RCTs (up to August 2012) representing 68,680 patients in primary and secondary prevention settings	Diet (2 RCTs) and supplemental (18 RCTs) marine n-3 fatty acids with a dose range of 0.53–1.80 g/d EPA + DHA (median EPA + DHA dose: 1 g/d)	1–6.2 years (median: 2 years)	No effect on all-cause mortality, cardiac death, sudden death, MI or stroke
Casula et al., 2013 [75]	11 RCTs (up to March 2013) representing 15,348 patients with CVD	Supplemental marine n-3 fatty acids with a dose range of 1–6 g/d EPA + DHA	≥ 1 year (duration ranged from 1–3.5 years)	32% reduction in cardiac death
				33% reduction in sudden death
				25% reduction in MI
				11% reduction in all-cause mortality (NS)
				No effect on stroke
Wen et al., 2014 [76]	14 RCTs (up to May 2013) representing 32,656 patients with CHD	Supplemental marine n-3 fatty acids with a dose range of 0.4–6.9 g/d EPA + DHA	< 3 months to 4.6 years	12% reduction in death from cardiac causes
				14% reduction in sudden cardiac death
				8% reduction in all-cause mortality
				7% reduction in cardiovascular events (NS)
Chowdhury et al., 2014 [21]	17 RCTs (up to June 2013) representing 76,580 participants	Supplemental marine n-3 fatty acids with a dose range of 0.3 g/d EPA to 6 g/d EPA + DHA.	0.1–8 years	7% reduction in coronary outcomes (NS)
Alexander et al., 2017 [22]	18 RCTs (up to November 2015)	Supplemental marine n-3 fatty acids with a dose range of 0.4–5.0 g/d EPA + DHA	0.5–7 years	14%–16% reduction in CHD in high-risk subgroups i.e., those with elevated triglycerides and LDL-cholesterol
Maki et al., 2017 [77]	14 RCTs (up to December 2016) representing 71,899 patients in a mixed/secondary prevention setting	Supplemental marine n-3 fatty acids with a dose range of 0.27–5.0 g/d EPA + DHA	≥ 6 months (range 0.5–6.2 years)	8% reduction in cardiac death
				~13%–29% reduction in cardiac death in the subgroup with high-risk individuals (secondary prevention, high triglycerides, high LDL-cholesterol and <40% statin use) and with EPA+DHA > 1 g/d
Aung et al., 2018 [78]	10 RCTs representing 77,917 high-risk patients (prior CHD or stroke)	Supplemental marine n-3 fatty acids with a dose range of 0.2–1.8 g/d EPA and 0–1.7 g/d DHA	1–6.2 years (mean: 4.4 years)	7% reduction in CHD death (NS)
				No effect on non-fatal MI, CHD events or major vascular events
Abdelhamid et al., 2018 [79]	79 RCTs (up to April 2017) representing 112,059 participants in primary and secondary prevention settings	Dietary or supplemental marine n-3 fatty acids with a dose range from 0.5 g/d to ~5 g/d EPA + DHA	1–7 years	7% reduction in CHD events
				No effect on all-cause mortality, cardiovascular mortality, cardiovascular events, CHD mortality, stroke or arrhythmia.

Abbreviations: CHD, coronary heart disease; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; LDL, low-density lipoprotein; MI, myocardial infarction; NS, not significant; RCT, randomised controlled trial.