JCL roundtable: Omega-3 fatty acids and cardiovascular outcomes.

The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) in 2018 demonstrated the value of an omega-3 fatty acid formulation, icosapent ethyl (eicosapentaenoic acid ethyl ester) for preventive treatment of atherosclerotic cardiovascular disease (ASCVD). This JCL Roundtable discussion brings together three experts to explore the origins and implications of REDUCE-IT and more broadly omega-3 fatty acids for mitigation of ASCVD risk. REDUCE-IT achieved a highly significant 25% reduction of major adverse cardiovascular events. It is the first trial of a triglyceride-lowering drug to gain unequivocal success in high-risk patients treated intensively with statins. It corroborates positive results from an earlier major trial using eicosapentaenoic acid (EPA) ethyl ester, the Japan EPA Lipid Intervention Study (JELIS), which included hypercholesterolemic subjects treated with low-dose statin mostly in primary prevention. Together these studies mark a new avenue for preventive treatment of ASCVD. Omega-3 fatty acids also show some promise, though less decisively, for reducing inflammation and cardiovascular mortality in a broader context.

National Lipid Association Scientific Statement on the use of icosapent ethyl in statin-treated patients with elevated triglycerides and high or very-high ASCVD risk.

Representatives from the National Lipid Association (NLA) participated in the development of the 2018 American Heart Association/American College of Cardiology/Multisociety Guideline on the Management of Blood Cholesterol, which reaffirmed that lifestyle changes and statin treatment are therapeutic cornerstones for atherosclerotic cardiovascular disease (ASCVD) risk reduction. It also updated prior recommendations to incorporate newer data demonstrating ASCVD risk reduction with ezetimibe and proprotein convertase subtilisin kexin type 9 inhibitors as adjuncts to statin therapy for patients at high and very-high ASCVD risk. The 2018 Guideline was finalized shortly before full results were available from a randomized, placebo-controlled cardiovascular outcomes trial [Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT)] that examined the effects of icosapent ethyl (IPE) 4 g/d on major adverse cardiovascular events in selected high- or very high-risk, statin-treated patients with elevated triglycerides. The primary outcome variable of first major adverse cardiovascular event (cardiovascular death, myocardial infarction, stroke, coronary revascularization and hospitalization for unstable angina) was reduced by 25% (95% confidence interval 17%-32%, P < .001). REDUCE-IT served as the primary basis for the NLA's review of evidence for the use of IPE for ASCVD risk reduction. Based on this review, the NLA position is that for patients aged ≥45 years with clinical ASCVD, or aged ≥50 years with diabetes mellitus requiring medication plus ≥1 additional risk factor, with fasting triglycerides 135 to 499 mg/dL on high-intensity or maximally tolerated statin therapy (±ezetimibe), treatment with IPE is recommended for ASCVD risk reduction (evidence rating: class I; evidence level: B-R).

Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association.

Hypertriglyceridemia (triglycerides 200-499 mg/dL) is relatively common in the United States, whereas more severe triglyceride elevations (very high triglycerides, ≥500 mg/dL) are far less frequently observed. Both are becoming increasingly prevalent in the United States and elsewhere, likely driven in large part by growing rates of obesity and diabetes mellitus. In a 2002 American Heart Association scientific statement, the omega-3 fatty acids (n-3 FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were recommended (at a dose of 2-4 g/d) for reducing triglycerides in patients with elevated triglycerides. Since 2002, prescription agents containing EPA+DHA or EPA alone have been approved by the US Food and Drug Administration for treating very high triglycerides; these agents are also widely used for hypertriglyceridemia. The purpose of this advisory is to summarize the lipid and lipoprotein effects resulting from pharmacological doses of n-3 FAs (>3 g/d total EPA+DHA) on the basis of new scientific data and availability of n-3 FA agents. In treatment of very high triglycerides with 4 g/d, EPA+DHA agents reduce triglycerides by ≥30% with concurrent increases in low-density lipoprotein cholesterol, whereas EPA-only did not raise low-density lipoprotein cholesterol in very high triglycerides. When used to treat hypertriglyceridemia, n-3 FAs with EPA+DHA or with EPA-only appear roughly comparable for triglyceride lowering and do not increase low-density lipoprotein cholesterol when used as monotherapy or in combination with a statin. In the largest trials of 4 g/d prescription n-3 FA, non-high-density lipoprotein cholesterol and apolipoprotein B were modestly decreased, indicating reductions in total atherogenic lipoproteins. The use of n-3 FA (4 g/d) for improving atherosclerotic cardiovascular disease risk in patients with hypertriglyceridemia is supported by a 25% reduction in major adverse cardiovascular events in REDUCE-IT (Reduction of Cardiovascular Events With EPA Intervention Trial), a randomized placebo-controlled trial of EPA-only in high-risk patients treated with a statin. The results of a trial of 4 g/d prescription EPA+DHA in hypertriglyceridemia are anticipated in 2020. We conclude that prescription n-3 FAs (EPA+DHA or EPA-only) at a dose of 4 g/d (>3 g/d total EPA+DHA) are an effective and safe option for reducing triglycerides as monotherapy or as an adjunct to other lipid-lowering agents.

Provider recommendations for patient-reported muscle symptoms on statin therapy: Insights from the Understanding Statin Use in America and Gaps in Patient Education survey.

BACKGROUND: Statin-associated muscle symptoms are reported by 10% to 29% of patients in clinical practice and are a major determinant of statin nonadherence, discontinuation, and switching. Little is known about what advice patients receive from their providers when dealing with these symptoms. OBJECTIVE: The objective of the study was to assess patient's reports of provider advice when experiencing new or worsened muscle symptoms while taking a statin. METHODS: Data were analyzed from the Understanding Statin Use in America and Gaps in Education survey, a self-administered internet-based survey of 10,138 adults with a reported history of high cholesterol and statin use. RESULTS: Of the respondents, 60% of former statin users (n = 1220) reported ever experiencing new or worsened muscle pain on a statin, in contrast to 25% of current users (n = 8918; P < .001). Former statin users reported stopping more statins because of muscle symptoms (mean ± standard deviation, 2.2 ± 1.7) compared with current users (mean 1.6 ± 1.5, P < .0001). For those with muscle-related symptoms while on a statin, participants reported that providers most often suggested switching to another statin (33.8%), stopping the statin (15.9%), continuing the statin with further monitoring of muscle symptoms (12.2%), reducing the statin dose (9.8%), or getting a blood test for signs of muscle damage (9.2%). A lower percentage were advised to add either vitamin D (7.0%) or coenzyme Q10 (5.8%), or to switch to nonstatin therapy (6.1%) or red yeast rice (2.6%). CONCLUSIONS: This study highlights patient experience with statin-associated muscle symptoms and the strategies recommended by providers in managing these symptoms. More research is needed to develop patient-centric and evidence-based approaches to managing statin-associated muscle symptoms, which is especially important in light of recent data showing increased cardiovascular risk among those who discontinue statin therapy.

Omega-3 Polyunsaturated Fatty Acid (Fish Oil) Supplementation and the Prevention of Clinical Cardiovascular Disease: A Science Advisory From the American Heart Association.

Multiple randomized controlled trials (RCTs) have assessed the effects of supplementation with eicosapentaenoic acid plus docosahexaenoic acid (omega-3 polyunsaturated fatty acids, commonly called fish oils) on the occurrence of clinical cardiovascular diseases. Although the effects of supplementation for the primary prevention of clinical cardiovascular events in the general population have not been examined, RCTs have assessed the role of supplementation in secondary prevention among patients with diabetes mellitus and prediabetes, patients at high risk of cardiovascular disease, and those with prevalent coronary heart disease. In this scientific advisory, we take a clinical approach and focus on common indications for omega-3 polyunsaturated fatty acid supplements related to the prevention of clinical cardiovascular events. We limited the scope of our review to large RCTs of supplementation with major clinical cardiovascular disease end points; meta-analyses were considered secondarily. We discuss the features of available RCTs and provide the rationale for our recommendations. We then use existing American Heart Association criteria to assess the strength of the recommendation and the level of evidence. On the basis of our review of the cumulative evidence from RCTs designed to assess the effect of omega-3 polyunsaturated fatty acid supplementation on clinical cardiovascular events, we update prior recommendations for patients with prevalent coronary heart disease, and we offer recommendations, when data are available, for patients with other clinical indications, including patients with diabetes mellitus and prediabetes and those with high risk of cardiovascular disease, stroke, heart failure, and atrial fibrillation.

Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management.

Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7-29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential.

Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: a review.

In this exploratory, hypothesis-generating literature review, we evaluated potentially differential effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and non-HDL-C in published studies of ω-3 fatty acid supplementation or prescription ω-3 fatty acid ethyl esters. Placebo-adjusted changes in mean lipid parameters were compared in randomized, controlled trials in subjects treated for ≥ 4 weeks with DHA or EPA. Of 22 studies identified, 6 compared DHA with EPA directly, 12 studied DHA alone (including 14 DHA-treated groups), and 4 examined EPA alone. In studies directly comparing EPA with DHA, a net increase in LDL-C of 3.3% was observed with DHA (DHA: +2.6%; EPA: -0.7%). In such head-to-head comparative studies, DHA treatment was associated with a net decrease in TG by 6.8% (DHA: -22.4%; EPA: -15.6%); a net increase in non-HDL-C by 1.7% (DHA: -1.2%; EPA -2.9%); and a net increase in HDL-C by 5.9% (DHA: +7.3%; EPA: +1.4%). Increases in LDL-C were also observed in 71% of DHA-alone groups [with demonstrated statistical significance (P < .05) in 67% (8 of 12) DHA-alone studies] but not in any EPA-alone studies. Changes in LDL-C significantly correlated with baseline TG for DHA-treated groups. The range of HDL-C increases documented in DHA-alone vs EPA-alone studies further supports the fact that HDL-C is increased more substantially by DHA than EPA. In total, these findings suggest that DHA-containing supplements or therapies were associated with more significant increases in LDL-C and HDL-C than were EPA-containing supplements or therapies. Future prospective, randomized trials are warranted to confirm these preliminary findings, determine the potential effects of these fatty acids on other clinical outcomes, and evaluate the generalizability of the data to larger and more heterogeneous patient populations.

Effects of eicosapentaenoic acid versus docosahexaenoic acid on serum lipids: a systematic review and meta-analysis.

Omega-3 fatty acid supplements containing both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to reduce triglycerides but also increase low-density lipoprotein (LDL). Whether EPA or DHA given as monotherapy has differential effects on serum lipoproteins has not been systematically evaluated. We performed a meta-analysis of randomized placebo-controlled trials of monotherapy with EPA (n=10), DHA (n=17), or EPA versus DHA (n=6). Compared with placebo, DHA raised LDL 7.23 mg/dL (95% CI, 3.98­10.5) whereas EPA non-significantly reduced LDL. In direct comparison studies, DHA raised LDL 4.63 mg/dL (95% CI, 2.15­7.10) more than EPA. Both EPA and DHA reduced triglycerides, with a greater reduction by DHA in direct comparison studies. DHA also raised high-density lipoprotein (4.49 mg/dL; 95% CI, 3.50­5.48) compared with placebo, whereas EPA did not. Although EPA and DHA both reduce triglycerides, they have divergent effects on LDL and high-density lipoprotein. Further research is needed to elucidate the mechanisms and significance of these differences.

Estimating health and economic benefits from using prescription omega-3 fatty acids in patients with severe hypertriglyceridemia.

Patients with increased triglyceride levels compared to those with normal levels are at higher risk for coronary heart disease. In patients with severe (≥500 mg/dl) hypertriglyceridemia (SHTG), clinical trials have demonstrated that prescription ω-3 fatty acids (P-OM3s) 4 g/day can decrease triglyceride levels by 45%. However, the precise health and economic benefits of decreasing SHTG with P-OM3 are unknown. We used the previously validated Archimedes model to simulate a 20-year trial involving subjects 45 to 75 years old with SHTG. The trial consisted of an intervention arm (P-OM3 4 g/day) and a control arm. Simulation results for the control arm indicated that subjects with SHTG are at about 2 times higher risk for myocardial infarction than those with normal triglyceride levels. Using estimates from previous epidemiologic studies and meta-analyses with OM3s, the model predicted 29% to 36% decreases in various measurements of adverse cardiac events for the intervention arm. The model also predicted a decrease in ischemic stroke of 24% (95% confidence interval 15 to 33). For the 20-year simulated trial, the cost per quality-adjusted life-year gained for the currently available P-OM3 approved by the Food and Drug Administration was $47,000. Results remained robust under different clinical assumptions. In our model P-OM3 was effective in decreasing triglyceride levels and cardiovascular disease risk in patients with SHTG. In conclusion, P-OM3 medication is cost effective in our simulated trial and comparable to other cost-effective cardiovascular interventions.

Omega-3 Fatty acids for cardiovascular disease prevention.

OPINION STATEMENT: Major dietary sources of omega-3 fatty acids are fish containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as nuts, seeds, and vegetable oils containing α-linolenic acid (ALA). Omega-3 fatty acids, especially those derived from marine sources, may be a useful tool for the primary and secondary prevention of cardiovascular disease. Omega-3s exert their cardioprotective effects through multiple mechanisms, including reducing arrhythmias and altering production of prostaglandins, which reduces inflammation and improves platelet and endothelial function. To date, no serious adverse effects of omega-3s have been identified, despite extensive study. In adults, any potential harm from mercury exposure from consuming fish rich in omega-3s is outweighed by the proven cardiovascular benefits of eating fish. Concerns over increased bleeding complications have not materialized despite the increased concomitant use of aspirin and clopidogrel. We recommend one serving (200-400 g) of fatty fish two times per week and a diet that includes foods rich in ALA for the primary prevention of cardiovascular disease. We recommend one serving (200-400 g) of fatty fish or a fish oil supplement containing 900 mg of EPA + DHA every day and a diet rich in ALA for patients with known cardiovascular disease or congestive heart failure.

Effect of baseline plasma fatty acids on eicosapentaenoic acid levels in individuals supplemented with alpha-linolenic acid.

We previously reported a >50% increase in mean plasma eicosapentaenoic acid levels in a general medicine clinic population after supplementation with alpha-linolenic acid. In the current analysis, we evaluate the variability of changes in eicosapentaenoic acid levels among individuals supplemented with alpha-linolenic acid and evaluated the impact of baseline plasma fatty acids levels on changes in eicosapentaenoic acid levels in these individuals. Changes in eicosapentaenoic acid levels among individuals supplemented with alpha-linolenic acid ranged from a 55% decrease to a 967% increase. Baseline plasma fatty acids had no statistically significant effect on changes in eicosapentaenoic levels acid after alpha-linolenic acid supplementation. Changes in eicosapentaenoic acid levels varied considerably in a general internal medicine clinic population supplemented with alpha-linolenic acid. Factors that may impact changes in plasma eicosapentaenoic acid levels after alpha-linolenic acid supplementation warrant further study.

Role of n-3 fatty acids in the treatment of hypertriglyceridemia and cardiovascular disease.

n-3 Fatty acids (FAs) when used in doses of 3-4 g/d eicosapentaenoic acid and docosahexaenoic acid have profound effects on triacylglycerol (TG) concentrations. The mechanism for their TG reduction relates to their favorable effects on reducing hepatic production and secretion of VLDL and VLDL apolipoprotein B particles, along with favorable effects on plasma lipolytic activity through lipoprotein lipase-mediated clearance, as well as stimulation of beta-oxidation of other FAs in the liver. Their hypotriglyceridemic properties are related to both the dose of n-3 FAs used and the baseline TG concentrations of the population. In patients with TG concentrations >500 mg/dL, 4 g n-3 FAs have been shown to reduce TGs by 45%, VLDL by 42%, and non-HDL by 10.2%. A recent pooled meta-analysis with multiple doses of n-3 FAs ranging from 0.8 to 5.4 g revealed changes in TGs of -27 mg/dL (95% CI: -33, -20), in HDL of +1.6 mg/dL (95% CI: + 0.8, +2.3), and in LDL cholesterol of +6 mg/dL (95% CI: + 3, +8). The clinical uses of n-3 FAs include treatment of severe and moderate hypertriglyceridemia, use in statin-treated patients with elevated TG concentrations or non-HDL cholesterol (mixed hyperlipidemia), and use in the secondary and primary prevention of cardiovascular disease. Existing large-scale clinical trials such as the GISSI-Prevenzione Study and JELIS with low doses of n-3 FAs (1-2 g) show clinical benefit in reducing coronary heart disease without substantial changes in concentrations of TGs or other lipids. Future clinical trials need to determine whether the TG-lowering doses of n-3 FAs (3-4 g/d) result in additional risk reduction.

Conclusions and recommendations from the symposium, Beyond Cholesterol: Prevention and Treatment of Coronary Heart Disease with n-3 Fatty Acids.

After the symposium "Beyond Cholesterol: Prevention and Treatment of Coronary Heart Disease with n-3 Fatty Acids," faculty who presented at the conference submitted manuscripts relating to their conference topics, and these are presented in this supplement. The content of these manuscripts was reviewed, and 2 conference calls were convened. The objective was to summarize existing evidence, gaps in evidence, and future research needed to strengthen recommendations for specific intakes of n-3 fatty acids for different conditions relating to cardiovascular disease. The following 2 questions were the main items discussed. What are the roles of n-3 fatty acids in primary versus secondary prevention of coronary heart disease? What are the roles of n-3 fatty acids in hypertriglyceridemia, in the metabolic syndrome and type 2 diabetes, and in sudden cardiac death, cardiac arrhythmias, and vulnerable plaque? Each area was summarized by using 2 general categories: 1) current knowledge for which general consensus exists, and 2) recommendations for research and policy. Additional references for these conclusions can be found in the articles included in the supplement.

Managing dyslipidemia in chronic kidney disease.

The incidence of chronic kidney disease (CKD) in the U.S. continues to increase, and now over 10% of the U.S. population has some form of CKD. Although some patients with CKD will ultimately develop renal failure, most patients with CKD will die of cardiovascular disease before dialysis becomes necessary. Patients with CKD have major proatherogenic lipid abnormalities that are treatable with readily available therapies. The severe derangements seen in lipoprotein metabolism in patients with CKD typically results in high triglycerides and low high-density lipoprotein (HDL) cholesterol. Because of the prevalence of triglyceride disorders in patients with CKD, after treating patients to a low-density lipoprotein goal, non-HDL should be calculated and used as the secondary goal of treatment. A review of the evidence from subgroup analysis of several landmark lipid-lowering trials supports treating dyslipidemia in mild to moderate CKD patients with HMG-CoA reductase inhibitors. The evidence to support treating dyslipidemia in hemodialysis patients, however, has been mixed, with several outcome trials pending. Patients with CKD frequently have mixed dyslipidemia and often require treatment with multiple lipid-lowering drugs. Although statins are the cornerstone of therapy for most patients with CKD, differences in their pharmacokinetic properties give some statins a safety advantage in patients with advanced CKD. Although most other lipid-lowering agents can be used safely with statins in combination therapy in patients with CKD, the fibrates are renally metabolized and require both adjustments in dose and very careful monitoring due to the increased risk of rhabdomyolysis. After reviewing the safety and dose alterations required in managing dyslipidemia in patients with CKD, a practical treatment algorithm is proposed.

Beyond lipids: the role of omega-3 fatty acids from fish oil in the prevention of coronary heart disease.

Omega-3 fatty acid therapy shows great promise in the secondary prevention of coronary artery disease. A meta-analysis of recent omega-3 trials shows reductions of coronary heart disease mortality of 36% (95% CI, 20%-50%; P<0.001) and total mortality of 17% (95% CI, 0%-32%; P=0.046). Some of the potential mechanisms for cardiovascular protection include a reduction in cardiac arrhythmias and plaque stabilization. Since the publication of the landmark GISSI-Prevenzione trial, there have been three major intermediate cardiovascular endpoint studies in patients with implantable cardioverter defibrillators (ICDs) and one large trial, the Japan EPA Lipid Interventional Study (JELIS) trial, which involved 18,645 Japanese patients in primary and secondary prevention. The three studies with ICD patients have been mixed, with favorable trends toward reduction in the incidence of ventricular arrhythmias in some but not all of the studies. Results of the recent JELIS trial in a Japanese population already consuming a high intake of omega-3 fatty acids showed a 19% risk reduction in major coronary events. Most of the reductions were in unstable angina and nonfatal coronary events, but not in sudden death and cardiovascular mortality. The totality of evidence suggests greater benefits with omega-3 fatty acids in secondary prevention than primary prevention and in populations consuming low amounts of omega-3 fatty acids.

Hypertriglyceridemia and cardiovascular risk reduction.

BACKGROUND: Elevated triglyceride (TG) levels are prevalent among the US population, often occurring in persons who are overweight or obese, or who have type 2 diabetes or the metabolic syndrome. There is evidence that elevated TG levels may be a significant independent risk factor for coronary heart disease (CHD), particularly in women. OBJECTIVE: This article reviews data on the epidemiology, associated risks, treatment, and prevention of hypertriglyceridemia, including recommended TG goals and available TG-lowering agents. METHODS: MEDLINE was searched for articles published from 1990 through 2006 using the terms hypertriglyceridemia, dyslipidemia, and coronary heart disease, with subheadings for risk, statins, niacin, fibrates, thiazolidinediones, and omega-3 fatty acids. The reference lists of relevant articles were examined for additional citations. Publications discussing the epidemiology of hypertriglyceridemia, CHD risk, treatment guidelines for lipid management, clinical trials involving TG-lowering drugs, and outcomes for lipid-modifying therapies were selected for review. RESULTS: Concern over the increasing rate of hypertriglyceridemia and its deleterious health consequences is reflected in the most recent National Cholesterol Education Program guidelines. Several lipid-lowering agents are available, including statins, fibrates, niacin, thiazolidinediones, and prescription omega-3 fatty acids. Clinical trials of these drugs have reported lowering of TG by 7% to 50%. Along with lifestyle changes, the use of combination pharmacotherapy to reduce lipid levels (including TG) may be an effective strategy in patients with dyslipidemia. CONCLUSION: Use of strategies to manage TG levels, along with low-density lipoprotein cholesterol levels, is warranted to help reduce the risk of CHD.

Flaxseed oil supplementation does not affect plasma lipoprotein concentration or particle size in human subjects.

alpha-Linolenic acid (ALA) is a major dietary (n-3) fatty acid. Some clinical trials with ALA supplementation have shown reduced cardiovascular risk; however the specific cardioprotective mechanism is not known. We studied the effects of daily supplementation with ALA derived from flaxseed oil on concentrations of plasma LDL cholesterol, HDL cholesterol, intermediate density lipoprotein cholesterol, and lipid particle sizes. In a randomized double-blind trial, 56 participants were given 3 g/d of ALA from flaxseed oil in capsules (n = 31) or olive oil containing placebo capsules (n = 25) for 26 wk. Changes in plasma HDL cholesterol, LDL cholesterol, and triglyceride concentrations did not differ between the 2 groups at 26 wk. The adjusted plasma total cholesterol concentration at 26 wk was 0.45 mmol/L higher in the flaxseed oil group (5.43 +/- 0.03 mmol/L) compared with the olive oil group (5.17 +/- 0.07 mmol/L) (P = 0.026). ALA did not affect LDL, HDL, or IDL particle size; however, the concentrations of the large, less atherogenic LDL1 (P = 0.058) and LDL2 (P = 0.083) subfractions tended to be greater in the ALA group. In conclusion, ALA does not decrease CVD risk by altering lipoprotein particle size or plasma lipoprotein concentrations.

Secondary prevention of coronary artery disease with omega-3 fatty acids.

Omega-3 fatty acid therapy is a promising intervention for the secondary prevention of coronary artery disease (CAD). Omega-3 fatty acids have properties that promote atherosclerotic plaque stability and decrease the incidence of ischemia-driven cardiac arrhythmias. A large number of clinical trials conducted in patients with CAD or prior myocardial infarction (MI) have examined hard cardiovascular end points, including total mortality, cardiovascular mortality, sudden death, and nonfatal MI. Several intermediate cardiovascular end-point studies have also examined whether ventricular arrhythmias can be suppressed in patients with implantable cardioverter defibrillators (ICDs). Significant reductions in total mortality and sudden death--20% to 50%--have been found in studies using doses of 0.85 to 4.0 g/day, with treatment durations from 12 to 42 months. Favorable trends toward reduction in the incidence of arrhythmic events have been demonstrated in some, but not all, ICD studies. Omega-3 fatty acid therapy shows a general positive trend toward benefit in reducing life-threatening events after MI and in patients with ICDs who have ischemic arrhythmias. Results of the recent Japan EPA Lipid Intervention Study (JELIS) in a large cohort (N = 18,645) of Japanese men and women suggest significant benefits in the reduction of unstable angina and nonfatal coronary events. The totality of evidence supports a strong role for omega-3 fatty acids derived from fish oil in secondary prevention through a presumptive role as an antiarrhythmic agent and through an ability to promote plaque stabilization.

Flaxseed oil increases the plasma concentrations of cardioprotective (n-3) fatty acids in humans.

Alpha-linolenic acid (ALA) is a major dietary (n-3) fatty acid. ALA is converted to longer-chain (n-3) PUFA, such as eicosapentaenoic acid (EPA) and possibly docosahexaenoic acid (DHA). EPA and DHA are fish-based (n-3) fatty acids that have proven cardioprotective properties. We studied the effect of daily supplementation with 3 g of ALA on the plasma concentration of long-chain (n-3) fatty acids in a predominantly African-American population with chronic illness. In a randomized, double-blind trial, 56 participants were given 3 g ALA/d from flaxseed oil capsules (n = 31) or olive oil placebo capsules (n = 25). Plasma EPA levels at 12 wk in the flaxseed oil group increased by 60%, from 24.09 +/- 16.71 to 38.56 +/- 28.92 micromol/L (P = 0.004), whereas no change occurred in the olive oil group. Plasma docosapentaenoic acid (DPA) levels in the flaxseed oil group increased by 25% from 19.94 +/- 9.22 to 27.03 +/- 17.17 micromol/L (P = 0.03) with no change in the olive oil group. Plasma DHA levels did not change in either group. This study demonstrates the efficacy of the conversion of ALA to EPA and DPA in a minority population with chronic disease. ALA may be an alternative to fish oil; however, additional clinical trials with ALA are warranted.

Usefulness of omega-3 fatty acids and the prevention of coronary heart disease.

Clinical trial evidence exists that supports a role for the omega-3 polyunsaturated fatty acids in coronary heart disease prevention. However, the results from these clinical trials have varied and were conducted in diverse population groups using several different types of omega-3 polyunsaturated fatty acids, including eicosapentaenoic acid, docosahexaenoic acid, and alpha-linolenic acid (ALA). Thus, we systematically reviewed previously published reports assessing the different types of omega-3 polyunsaturated fatty acid interventions and cardiovascular outcomes. Fourteen randomized clinical trials were included in the review. Six trials were included with fish oil, with 1 large trial (10,000 patients) dominating the analysis. In aggregate, the fish oil trials demonstrated a reduction in total mortality and sudden death without a clinically significant reduction in nonfatal myocardial infarction. The 6 trials with ALA supplements or an ALA-enriched diet were of poorer design than the fish oil trials and had limited power. Many of the trials with ALA involved other changes in dietary components. In aggregate, the ALA trials demonstrated possible benefits in reducing sudden death and nonfatal myocardial infarction, but with wider confidence intervals than in the fish oil trials. In conclusion, the evidence suggests a role for fish oil (eicosapentaenoic acid, docosahexaenoic acid) or fish in secondary prevention because recent clinical trial data have demonstrated a significant reduction in total mortality, coronary heart disease death, and sudden death. The data on ALA have been limited by studies of smaller sample size and limited quality.