Table 2.

Salient studies illustrating decision points for use of O3FAs in reducing residual risk in patients who are appropriately prescribed statins

TRIAL, NO. OF PARTICIPANTS, DATE, 1° OR 2° PREVENTION	POPULATION	FORMULATION	STATIN USE	PRIMARY END POINT	HR FOR 1° END POINT	RELATIVE WEIGHT (KHAN ET AL16=0)
Older EPA and DHA trials using statins suboptimally by current standards
GISSI-Prevenzione17 N=11,324 1999 2° prevention	Recent MI	EPA and DHA ethyl esters 850 mg/d	5% at onset Up to 46% at completion	Death, nonfatal MI, nonfatal stroke	0.85 (95% CI 0.74-0.98) P=.023	41.5% of EPA and DHA trials
GISSI-Heart Failure18 N=6975 2008 2° prevention	CHF classes II to IV	EPA and DHA ethyl esters 850 mg/d	23%	Death or CVD, or hospitalized for CHF	0.92 (95% CI 0.849-0.999) P=.009
More recent EPA and DHA trials using more optimized statin dosing
VITAL22 N=25,871 2019 1° prevention	Men aged ≥50 y Women aged ≥55 y	Marine O3FA 1 g/d 460 mg EPA 380 mg DHA	50% Included low-risk participants	MACE	0.92 (95% CI 0.80-1.06) P=.24	58.5% of EPA and DHA trials
ASCEND23 N=15,480 2018 1° prevention	Age >40 y with diabetes	Marine O3FA 1 g/d 460 mg EPA 380 mg DHA	75%	Nonfatal MI, stroke, TIA, vascular death	0.97 (95% CI 0.87-1.08) P=.55
OMEMI15 N=1027 2021 2° prevention	Aged 70 to 82 with acute MI	EPA and DHA ethyl esters 1.8 g/d	96.5%	Nonfatal MI, revasc, stroke, all-cause death, or hospitalized for CHF	1.08 (95% CI 0.82-1.41) P=.60
STRENGTH12 N=13,078 2020 Mixed 1° and 2° prevention	Age >18 y High CVD risk High TG levels Low HDL-C levels	EPA and DHA carboxylic acids 4 g/d	100%	CVD death, nonfatal MI, stroke, revasc, or hospitalized for angina	0.99 (95% CI 0.90-1.09) P=.84
EPA-only trials
JELIS24 N=18,645 2008 1° prevention	High serum cholesterol level	Icosapent ethyl (EPA) 1.8 mg/d	100%	MACE	0.81 (95% CI 0.69-0.95) P=.011	EPA-only trials
REDUCE-IT6 N=8179 2019 Mixed 1° and 2° prevention	High CVD risk and age >45 y or diabetes and age >50 y and TG 1.5-5.6 mmol/L and LDL-C 1.1-2.6 mmol/L	Icosapent ethyl (EPA) 4 g/d	100%	CVD death, nonfatal MI, nonfatal stroke, unstable angina, or revasc	0.75 (95% CI 0.68-0.83) P<.001

ASCEND—A Study of Cardiovascular Events in Diabetes, CHF—congestive heart failure, CVD—cardiovascular disease, DHA—docosahexaenoic acid, EPA—eicosapentaenoic acid, GISSI—Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico, HDL-C—high-density lipoprotein cholesterol, HR—hazard ratio, JELIS—Japan EPA Lipid Intervention Study, LDL-C—low-density lipoprotein cholesterol, MACE—major adverse cardiovascular events, MI—myocardial infarction, O3FA—omega-3 fatty acid, OMEMI—Omega-3 Fatty Acids in Elderly with Myocardial Infarction, REDUCE-IT—Reduction of Cardiovascular Events with EPA-Intervention Trial, revasc—revascularization, STRENGTH—Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia, TG—triglyceride, TIA—transient ischemic attack, VITAL—Vitamin D and Omega-3 Trial.

Data from Khan et al.¹⁶