The Role of Long-Chained Marine N-3 Polyunsaturated Fatty Acids in Cardiovascular Disease

Table 2

(a) Major clinical trial data for primary and secondary prevention of cardiovascular disease. (b) Major clinical trial data on antiarrhythmic end points.

(a)

Study	Dose of FAs	Control	𝑁	Followup	Prior MI/CAD	Mortality			Nonfatal MI	All CVDevents	Stroke
						All-cause	Cardiac	SCD
RCTs, blinded
Omega [54]	1 g/d n-3 FAs	1 g Olive oil	3851	1 Year	100%	1.25; (0.90–1.72)		0.95; (0.56–1.60)		1.21; (0.96–1.52)
Alpha Omega; Trial [55]	226 mg EPA +; 150 mg DHA	1.9 g ALA or placebo	4837	40 Months	100%	1.01; (0.82–1.24)	0.95; (0.68–1.32)			1.1; (0.87–1.17)
GISSI-HF [56]	1 g/d n-3 FAs	Placebo	6975	3.9 Years	41.8%	0.91; (0.83–0.99)		0.93; (0.79–1.08)
ORIGIN [64]	1 g n-3 FAs	1 g Olive oil	12536	6 Years	59%	0.98; (0.89–1.07)		1.10; (0.93–1.30)		1.01; (0.93–1.10)	0.92; (0.79–1.08)
OFAMI [74]	4 g n-3 FAs	4 g Corn oil	300	18 Months	100%	1.0; (0.45–2.2)		1.0; (0.39–2.6)	1.4; (0.7–2.6)		1.1; (0.84–1.3)
IEIS-4 [67]	1.08 g EPA	2.9 ALA or placebo	360	1 Year	100%		0.52; (0.29–0.95)	0.24; (0.05–1.1)	0.52; (0.3–0.9)	0.71; (0.48–1.1)
RCTs, unblended
DART [52]	Fish 200–400 g/week	Fruits and vegetables	2033; male	2 Years	100%	0.71; (0.54–0.93)				0.84; (0.66–1.07)
GISSI [53]	1 g/d n-3 FAs	Vitamin E or placebo	11324	3.5 Years	100%	0.79; (0.66–0.93)	0.65; (0.51–0.82)	0.55; (0.51–0.82)	0.91 (0.68–0.94)	0.80; (0.68–0.94)	1.2; (0.81–1.9)
JELIS [61]	1800 mg EPA	Statin	18645	4.6 Years	20%	1.09; (0.92–1.28)	0.94; (0.57–1.56)	1.06; (0.55–2.07)	0.75 (0.54–1.04)	0.81; (0.69–0.95)	1.02; (0.91–1.13)
DART 2 [75]	2 meals of fish/week or 3 g; n-3 FA suppl.	Intake of fruits, vegetables, and oats	3114	3–9 Years	100%	1.15; (0.96–1.36)	1.26; (1.0–1.56)	1.54; (1.06–2.23)
Observational
Nurses’ Health; Study [66]	Intake of fish; (meals/week)		84688	16 Years	0%		0.55; (0.33–0.90)		0.73; (0.51–1.04)	0.66; (0.50–0.89)
The Physicians’ health study [71]	Intake of fish; (meals/week)		21185	4 Years						1.2; (0.6–2.2)
The Zutphen study [70]	Intake of fish; (meals/week) or estimated EPA + DHA/d		1373	40 Years	0%		0.73; (0.47–1.13)	0.89; (0.34–2.30)
JPHC study [60]	Quintiles of fish intake		41578	10 Years	0%		1.08; (0.42–2.76)	1.14; (0.36–3.63)	0.43; (0.23–0.81)
WENBIT [63]	Quartiles of; n-3 FA intake		2412	57 Months	90%	1.11 (0.73–1.67)	1.35; (0.75–2.42)

(b)

Study	Inclusion criteria	Prior MI/CAD	Dose of FAs	Control	𝑁	Followup	Endpoint	Event rate (%)
RCTs, blinded
Leaf et al. [47]	ICD due to SCA, spontaneous or inducible sustained VT.	78%	4 g/day; n-3 FAs	4 g corn oil	402	12 months	Time to first ICD-event for VT/VF	Rate of ICD-event: 28% (n-3 FAs) versus 39%, RR 0.67 (0.47–0.95)
Brouwer et al. [78]; (SOFA)	One episode of spontaneous VT or VF in the preceding year, ICD implanted	70%	0.9 g/day; n-3 FAs	2 g high-oleic acid sun-lower oil	546	12 months	Appropriate ICD intervention for VT or VF, or all-cause death	30% versus 33% with sustained ICD intervention or death; HR 0.86 (0.64–1.16)
Finzi et al. [79]; (GISSI-HF)	ICD due to SCA, sustained VT or for primary prevention of syncope.	41.7%	1 g/day; n-3 FAs	Placebo	566	928 days	Incidence of ICD-interventions	ICD events 27.3% versus 34.0%, HR 0.80 (0.59–1.09). Mortality 26.6% versus 24.3%, HR 1.25 (0.89–1.75)
Raitt et al. [80]	ICD and a recurrent episode of VT or VF.	73%	1.8 g/day; n-3 FAs; (1.3 g EPA/; DHA)	Olive oil; (73% oleic acid)	200	2 years	Time to first ICD-event for VT/VF and frequency of recurrent VT/VF events	65% versus 59% with ICD therapy. Recurrent VT/VF more common in n-3 FA group (𝑃<0.001)
RCTs, non-blinded
Madsen et al. [81]	Inducible sustained monomorphic VT	83%	3.9 g; n-3 FAs	0.9% saline	6		Level of stimulation required to induce monomorphic VT	2 of 6 noninducible; 2 of 6 increased stimulation required
Intervention studies, non-randomized
Schrepf et al. [45]	Repeated episodes of sustained VT	90%	3.8 g; n-3 FAs as IV infusion		10		Inducibilty of sustained VT in patients with a positive test at baseline	2 of 7 patients (29%)
Metcalf et al. [44]	ICD and inducible sustained monomorphic VT	100%	3 g/day; n-3 FAs	No dietary manipulation	26	6 weeks	Level of stimulation required to induce monomorphic VT	42% versus 7% without inducible VT.
Observational
Aarsetoey et al. [82]	SCA with documented VF during the ischemic phase of an MI	100%	Blood omega-3 index	Omega-3 index in MI patients without SCA	195		The omega-3 index in SCA patients versus MI patients free of SCA	1% increase of the omega-3 index associated with 48% reduction in risk of VF

RCT: randomized controlled trial, EPA: eicosapentaenoic acid, DHA: docosahexaenoic acid, ALA: alpha-linolenic acid, VT: ventricular tachycardia, VF: ventricular fibrillation, and SCA: sudden cardiac arrest.