5 Introduction
5.2 Marine n-3 polyunsaturated fatty acids in patients with chronic kidney disease and other patient
Although large epidemiological studies report inconsistent results (Table 3), most of the studies suggest an overall negative association between fish consumption and cardiovascular morbidity and mortality (9, 88-102). For decades, concordant evidence from interventional studies also suggested cardio-protective effects of marine n-3 PUFAs (4). This view has been challenged in recent meta-analyses of RCTs (103-105), indicating no significant effects of marine n-3 PUFA supplementation on cardiovascular morbidity or mortality. These meta-analyses were hampered by substantial heterogeneity, received critique for their selection of studies (106) and other meta-analyses of RCTs reached the opposite conclusion (107, 108).
Nonetheless, the evidence for additional cardioprotective effects of marine n-3 PUFAs to optimal anti-thrombotic, anti-hypertensive and statin therapy is unclear, as most RCTs performed after the year 2000 have failed to show significant beneficial effects of marine n-3 PUFA supplementation on cardiovascular morbidity and mortality (78, 109-121). These drugs share many of the beneficial effects of marine n-3 PUFAs (4, 30, 37). However, some patient populations might benefit from a high marine n-3 PUFA intake, including patients with dyslipidemia (78), chronic kidney disease (32, 79, 122) and transplant recipients (123-129).
In patients on hemodialysis therapy, plasma marine n-3 PUFA levels were negatively associated with the risk of SCD (79) and marine n-3 PUFA supplementation reduced the incidence of myocardial infarction (MI) (122). Marine n-3 PUFA supplementation have been found to slow down the decline in renal function in patients with IgA nephritis (32). Improved renal function after marine n-3 PUFA supplementation has also been reported in patients without renal disease (117, 124, 127). Marine n-3 PUFA supplementation has also been shown to improve arteriovenous graft patency (41, 130, 131) and most studies in ESRD patients report a modest improvement of lipid profile (38, 130, 132-137).
A few interventional studies have investigated the effects of marine n-3 PUFAs after cardiac transplantation, and report improved lipid profile, lower blood pressure and lower resting heart rate (123-126). Studies on the effects of marine n-3 PUFAs in liver and bone marrow transplant recipients are scarce, but promising (127-129). To our knowledge, no study has investigated the effects of marine n-3 PUFAs in skin or lung transplantation. Due to possible gastrointestinal side-effects (74), marine n-3 PUFAs are probably not the drug of choice in intestinal or pancreas transplant recipients.
Table 3. Effects of marine n-3 polyunsaturated fatty acids in patient populations other than renal transplant recipients.
Ref Yr First author Country Study population, design, sample size, follow-up time and findings Epidemiological studies in the general population
(88) 86 Norell Sweden Twin registry, n=10,966, DQ, 14yr follow-up. Lower cardiovascular mortality.
(89) 95 Ascherio US Health Professionals Study. Men 45-85yr, n=44,895, DQ, up to 11yr follow-up. No association with coronary artery disease incidence.
(90) 98 Albert US Physicians Health Stud. Men 40-85yr, DQ, n=20,551. Lower overall mortality, lower SCD incidence, but no effect on cardiovascular mortality.
(91) 02 Albert US Physicians Health Study, nested case control study, n=278. Less SCD with increasing plasma marine n-3 PUFA levels.
(102) 97 Daviglus US Chicago Western Electric Study. Men 40-55yr, n=1,822, dietary interview, mean follow-up 26yr. Lower cardiovascular mortality.
(92) 97 Pietinen Finland Men 50-70yr who were current smokers, n=21,930, DQ, 6yr follow-up.
Non-significant tendency towards increased mortality.
(93) 01 Yuan China Men 45-65yr, n=18,244, DQ, 12yr follow-up. Lower overall mortality, but no association with cardiovascular mortality.
(100) 01 Iso US Nurses’ Health Study. Women 35-60yr, n=79,839, DQ, 14yr follow-up. Higher fish consumption; lower stroke risk in non-aspirin users.
(98) 02 Hu US Nurses’ Health Study. Lower risk of coronary artery disease and cardiovascular mortality.
(99) 08 Sun US Nurses’ Health Study. Nested case control study, n=434. Lower risk of MI, lower triglyceride and higher HDL cholesterol levels with higher EPA and DHA, but not with DPA levels
(95) 05 Mozaffarian US Cardiovascular Health Study. Age ≥65yr, n=45,722, DQ, 14yr follow-up. Lower incidence of coronary artery disease.
(96) 05 Mozaffarian US Cardiovascular Health Study. Lower incidence of heart failure.
(94) 06 Iso Japan JPHC. Age 40-60yr, n=41,578, DQ, 11yr follow-up. Lower risk of coronary artery disease.
(9) 08 Sekikawa Japan Japanese in Japan, Japanese in US, Whites in US, cross-sectional study, n=868. The “Japanese” factor is related to a diet rich in marine fatty acids; lower carotid artery thickness and coronary artery calcification.
(97) 10 Bjerregaard Denmark Age 50-65yr, n=57,053, DQ, 7.5yr follow-up. Lower risk of coronary artery disease in men, but not in women.
(101) 10 Pottala US Heart and Soul Study. Adult patients, n=956, fatty acid analysis, 5.9yr follow-up. Higher marine n-3 PUFA levels were associated with lower mortality risk.
Interventional studies in the general population
(121) 10 Einvik Norway DOIT. RCT, men 65-75yr (28% established CVD), n=563, 2.1 g EPA+DHA vs corn oil for 3yr. Non-significant tendency towards lower overall and cardiovascular moratlity.
(120) 13 Roncaglioni Italy RCT, patients at high risk of CVD, n=12,513, 0.8 g EPA+DHA vs olive oil for 5yr. No effect on cardiovascular morbidity and mortality.
Diabetes
(119) 13 Bosch Netherl. ORIGIN. RCT, patients at high risk of CVD, n=12,513, 0.8 g EPA+DHA vs olive oil for 5yr. No effect on cardiovascular morbidity and mortality.
Table 3 continued.
Ref Yr First author Country Study population, design, sample size, follow-up time and findings Cardiovascular disease
(110) 89 Burr UK DART 1. RCT, MI survivors, n=2,033, dietary advice or supplements (0.2-0.9 g EPA+DHA) vs no dietary advice, 2yr follow-up. Lower overall mortality, but no effect on MI incidence or cardiovascular mortality.
(109) 03 Ness UK DART 2. No long-term benefits in participants from the first study.
(138) 96 Eritsland Norway RCT, patients who underwent coronary artery bypass grafts, n=610, 1yr follow-up. Lower incidence of vein graft occlusion.
(139) 99 Johansen Norway RCT, patients who underwent percutaneous transluminal coronary angioplasty, n=529, 26w follow-up. No effect on restenosis incidence.
(111) 99 Marchioli Italy GISSI-Prevenzione. RCT, MI survivors, n=11,324, 0.9 g EPA+DHA vs vitamin E vs placebo for 3.5yr. Lower incidence of composite endpoint; myocardial reinfarction, stroke or mortality.
(112) 08 Tavazzi Italy GISSI-Heart Failure. RCT, patients with heart failure, n=6,920, 0.9 g EPA+DHA vs vitamin E vs placebo for 4yr. Lower overall and cardiovascular mortality.
(140) 01 Nilsen Norway RCT, MI survivors, n=300, 3.6 g EPA+DHA vs corn oil for a median of 1.5yr. Higher HDL cholesterol, lower triglycerides, but no effect on composite major cardiovascular event and mortality endpoint.
(141) 03 Erkkilä Finland Observational cohort study, established coronary artery disease, n=415, fatty acid analysis, 5yr follow-up. Lower overall mortality with higher EPA and DHA, EPA also associated with cardiovascular mortality.
(113) 06 Brouwer Netherl. RCT, patients with ICD after documented ventricular arrhythmia, n=546, 0.8 g EPA+DHA for 1yr. Non-significant tendency towards less ICD intervention due to ventricular arrhythmia.
(114) 10 Galan France SU.FOL.OM3. RCT, patients with history of ischemic heart disease or stroke, n=2,501, 0.6 g EPA+DHA vs vitamin B vs placebo for 5yr. No effect on composite endpoint (MI, stroke or cardiovascular mortality).
(118) 10 Rauch Germany OMEGA. RCT, MI survivors, n=3,851, 0.8 g EPA+DHA vs olive oil for 1yr. No effect on major cardiovascular events or mortality.
(115) 10 Kromhout Netherl. Alpha Omega. RCT, MI survivors, n=4,837, 0.4 g EPA+DHA vs placebo for 3.5yr. No effect on major cardiovascular events.
(116) 12 Eussen Netherl. Alpha Omega. Reduced major cardiovascular events in non-statin users.
(117) 14 Hoogeveen Netherl. Alpha Omega. Improved renal function.
Renal disease
(122) 06 Svensson Denmark RCT, ESRD, n=206, 1.7 g EPA+DHA vs olive oil for 2yr. Lower incidence of MI and lower triglyceride levels.
(79) 13 Friedman US Matched case control study, ESRD, n=400 (out of 10,044). Lower odds of SCD with higher levels of marine n-3 PUFAs.
(32) 94 Donadio US RCT, IgA nephritis, n=106, 3.2 g EPA+DHA vs olive oil for 2yr. Less decline in renal function compared with placebo.
(38) 99 Ando Japan RCT, ESRD, n= 38, 1.6 g EPA vs placebo for 18w. Lower levels of oxidized LDL cholesterol and remnant lipoproteins as well as lower triglyceride levels.
(41) 02 Schmitz US RCT, ESRD, n=24 , 3.2 g EPA+DHA vs corn oil for 1yr. Better arteriovenous graft patency, lower systemic BP and lower venous outflow resistance.
Table 3 continued.
Ref Yr First author Country Study population, design, sample size, follow-up time and findings Dyslipidemia
(78) 07 Yokoyama Japan JELIS. RCT, n=14,981, 1.8 g EPA+statin vs statin alone for 4.5yr.
Lower triglycerides and lower cardiovascular mortality, but no effect on SCD incidence.
Heart, liver and bone marrow transplantation
(125) 93 Ventura US RCT, heart transplantation, n=20, 3.0 g EPA+DHA vs corn oil for 52w.
Lower mean arterial BP and lower left ventricular mass.
(123) 97 Andreassen Norway RCT, heart transplantation, n=30, 3.4 g EPA+DHA vs corn oil for 27w.
Lower triglyceride levels, lower systolic and diastolic BP.
(124) 01 Holm Norway RCT, heart transplantation, n=55, 3.4 g EPA+DHA vs corn oil for 52w.
Improved renal function, lower systemic vascular recistance.
(126) 06 Harris US Clinical study, heart transplantation, n=18, 1.0 to 3.4 g EPA+DHA for 16 to 27w. Lower resting heart rate.
(127) 95 Badalamenti Italy RCT, liver transplantation, n=27, 3.5 g EPA+DHA vs corn oil for 8w.
Better renal blood flow, lower urine thromboxane A2 levels.
(128) 12 Zhu China Clinical study, liver transplantation, n=66, Parenteral EPA+DHA for 1w vs standard care. Improved patient survival and graft function.
(129) 01 Takatsuka Japan Clinical study, bone marrow transplantation, n=17, 1.8 g EPA vs no placebo for 30w. Improved patient survival, less severe GVHD.
Ongoing interventional studies
ORENTRA Renal transplant recipients, n=132, 2.7 g EPA+DHA vs olive oil for 44w. Detailed description of study design in section 10.
OMEMI MI survivors, n=1400, 1.8 g EPA+DHA vs corn oil for 2yr. Composite primary endpoint: Death, new non-fatal MI, revascularization or stroke
VITAL General population >50yr, n=25,874, 1.0 g EPA+DHA vs vitamin D vs combined treatment vs placebo, mean duration 5yr, for primary prevention of CVD and cancer ASCEND Diabetes, n=15,480, aspirin with either 1.0 g EPA+DHA or placebo for a minimum of
5yr. Primary endpoints fatal and non-fatal MI and strokes
Reduce-It Mixed dyslipidemia, high risk of / established CVD, n=8,000, statins with or without EPA, mean duration 5yr. Composite cardiovascular morbidity /mortality endpoint SuperiorSVG Coronary artery (saphenous vein) graft bypass, n=1,550, 1.1 g EPA+DHA vs placebo
for 1 yr, for prevention of graft occlusion and cardiovascular mortality
EPA: Eicosapentaenoic acid. DHA: Docosahexaenoic acid. BP: Blood pressure. MI: Myocardial infarction.
SCD: Sudden cardiac death. DQ: Dietary questionnaire. Ig: Immunoglobulin. Netherl.: Netherlands. n: number.
w: weeks. g: grams. yr: years. RCT: Randomized controlled trial. ESRD: End-stage renal disease. GVHD: Graft versus host disease. ORIGIN: Outcome reduction with initial glargine intervention. SU.FOL.OM3:
Supplementation with folate, vitamin B6, vitamin B12 and / omega-3 fatty acids trial. JELIS: Japan Eicosapentaenoic acid Lipid Intervention Study. GISSI: Gruppo Italiano per lo Studio della Soprawivenza nell’Infarcto Miocardio Prevenzione Trial. DART: Diet and Reinfarction Trial. DOIT: Diet and Omega-3 Interventional Trial. JPHC: Japan public health center-based prospective study. OMEMI: Omega-3 fatty acids in elderly patients with acute myocardial infarction. SuperiorSVG: Superior saphenous vein graft trial. VITAL:
Vitamin D and omega-3 trial. ASCEND: A study of cardiovascular events in diabetes. ORENTRA: Omega-3 fatty acids in renal transplantation.