More Recent Headlines from the Late-breaking Clinical Trial Presentations at the American Heart Association Scientific Sessions 2

More Recent Headlines from the Late-breaking Clinical Trial Presentations at the American Heart Association Scientific Sessions -

Less Pessimism Called for When Interpreting the Results from VITAL Regarding Cardiovascular Benefits with Omega-3

 

By Kevin C Maki, PhD and Mary R Dicklin, PhD

 The primary results from the Vitamin D and Omega-3 Trial (VITAL) were recently presented at the late-breaking clinical trial sessions of the American Heart Association (AHA) meeting in Chicago, IL and simultaneously published in the New England Journal of Medicine.1  VITAL was a randomized, placebo-controlled trial of a 1 g/d fish oil capsule (Lovaza®/Omacor®) and 2000 IU/day vitamin D3 administered to 25,871 men ≥50 y of age and women ≥55 y of age.  The primary endpoints were major cardiovascular events (a composite of myocardial infarction [MI], stroke or death from cardiovascular causes) and invasive cancer of any type.  The key secondary endpoints were individual components of the composite cardiovascular endpoint, the composite endpoint plus coronary revascularization, site-specific cancers and death from cancer.  Patients were followed for a median of 5.3 y.  A discussion of the findings from the omega-3 and cardiovascular disease portion of the trial follows.

A major cardiovascular event occurred in 386 subjects in the omega-3 group and 419 in the placebo group (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.80 to 1.06, p = 0.24).1  The HR (95% CI) for the key secondary endpoints were 0.93 (0.82 to 1.04) for the composite plus coronary revascularization, 0.72 (0.59 to 0.90) for total MI, 1.04 (0.83 to 1.31) for total stroke, and 0.96 (0.76 to 1.21) for death from cardiovascular causes.  There were no excess risks of bleeding or other serious adverse events with the interventions.

In our opinion, the response to the results from VITAL has been unnecessarily pessimistic.2  It is true that the 8% reduction in the primary composite endpoint was not statistically significant.  However, as we have previously written, we believe that the failure of many of the omega-3 cardiovascular outcomes trials to show clear evidence of benefit can likely be attributed, in part, to the low dosages of omega-3 administered (most <1 g/d eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]) and the groups in which the studies have been conducted (without elevated triglycerides [TG] and not limited to subjects with low omega-3 dietary intake).3  This was also the case in VITAL, where subjects at relatively low cardiovascular risk were administered a 1g/d fish oil concentrate capsule (providing 840 mg/d EPA + DHA) and the median fish intake in the study sample at baseline was well above the average intake in the US general population.1

 Results from the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), presented in the same late-breaking clinical trials session at AHA and published simultaneously in New England Journal of Medicine, demonstrated that Vascepa® at a higher dosage of 4 g/d (~3700 mg/d EPA as icosapent ethyl) administered to subjects at higher risk with elevated TG (median of 216 mg/dL) resulted in a significant 25% reduction in the primary endpoint, the composite of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization or unstable angina.4  Unfortunately, an editorial that accompanied VITAL did not acknowledge the findings from REDUCE-IT, and in fact stated “…in the absence of additional compelling data, it is prudent to conclude that the strategy of dietary supplementation with either n-3 fatty acids or vitamin D as protection against cardiovascular events or cancer suffers from deteriorating VITAL signs.”2  It would seem that we do have “additional compelling data” in REDUCE-IT and that we should not abandon the idea that omega-3 fatty acids, when administered at higher dosages and to higher risk populations, reduces cardiovascular risk.  This adds to the biologic plausibility of the secondary outcomes for which benefits were observed.

In VITAL, endpoints that achieved nominal statistical significance included reductions in total MI (HR 0.72, 95% CI 0.59 to 0.90), total coronary heart disease (composite of MI, coronary revascularization and death from coronary heart disease; HR 0.83, 95% CI 0.71 to 0.97) and death from MI (HR 0.50, 95% CI 0.26 to 0.97) with omega-3 fatty acids vs. placebo.1  However, the editorial that accompanied VITAL emphasized the strong need for caution in interpreting “positive” results from secondary endpoints.2  While we agree that statistically significant secondary endpoints should not outweigh the null findings from the primary endpoint, it is also important that findings from secondary endpoints are not overlooked, particularly when they are in general agreement with results from prior studies.3,5-7  It is also notable that the subgroup with below-median fish intake at baseline showed statistically significant reductions of 19% and 40% in the primary outcome variable and total MI, respectively.1  This observation further supports the possibility that a relatively low dosage of EPA + DHA may have benefits in those with lower omega-3 fatty acid intakes.8

Our group published a meta-analysis of 14 randomized controlled trials that investigated the effects of omega-3 fatty acid supplementation on cardiac death, and reported that there was an 8% lower risk with omega-3 fatty acids vs. controls (and ~29% lower risk when dosages >1 g/d EPA + DHA were evaluated).7  Death from CHD in VITAL was not statistically significantly lower (HR 0.76, 95% CI 0.49 to 1.16).1  However, to further assess the potential for fatal CHD reduction with omega-3 fatty acid supplementation, we added the results from VITAL,1 along with other recently published trials,4,6 to a previous meta-analysis published by Aung and colleagues.5  This analysis demonstrated a statistically significant reduction in fatal CHD with omega-3 fatty acid interventions (relative risk 0.901, 95% CI 0.841 to 0.965, p = 0.003).9

Thus, it is our opinion that the null findings for the primary cardiovascular endpoint in VITAL need to be interpreted alongside the favorable findings from REDUCE-IT.  These results suggest the need for additional studies with higher dosages of EPA + DHA administered to high-risk populations.  We eagerly await the results from the last of the large-scale omega-3 fatty acid trials that is underway, The Outcomes Study to Assess Statin Residual Risk Reduction with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia (STRENGTH), which enrolled subjects with elevated TG and below-average high-density lipoprotein cholesterol levels.10

References:

  1. Manson JE, Cook NR, Lee IM, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 2018; Epub ahead of print.

 

  1. Keaney JF, Jr., Rosen CJ. VITAL signs for dietary supplementation to prevent cancer and heart disease. N Engl J Med. 2018; Epub ahead of print.

 

  1. Maki KC, Dicklin MR. Omega-3 fatty acid supplementation and cardiovascular disease risk: glass half full or time to nail the coffin shut? Nutrients. 2018;10(7).

 

  1. Bhatt DL, Steg G, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2018; Epub ahead of print.

 

  1. Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: meta-analysis of 10 trials involving 77917 individuals. JAMA Cardiol. 2018;3:225-234.

 

  1. ASCEND Study Collaborative Group. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018; Epub ahead of print.

 

  1. Maki KC, Palacios OM, Bell M, Toth PP. Use of supplemental long-chain omega-3 fatty acids and risk for cardiac death: an updated meta-analysis and review of research gaps. J Clin Lipidol. 2018;11:1152-1160.

 

  1. Rimm EB, Appel LJ, Chiuve SE, et al. Seafood long-chain n-3 polyunsaturated fatty acids and cardiovascular disease: a science advisory from the American Heart Association. Circulation. 2018;138:e35-e47.

 

  1. Maki KC, Dicklin MR. Recent headlines from the late-breaking clinical trial presentations at the American Heart Association scientific sessions. REDUCE-IT – a landmark cardiovascular outcomes study of an omega-3 fatty acid. November 27, 2018. Available at https://mbclinicalacademy.com/headlines/.

 

  1. Nicholls SJ, Lincoff AM, Bash D, et al. Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: rationale and design of the STRENGTH trial. Clin Cardiol. 2018; 41:1281-1288.

 

 

 

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Recent Headlines from the Late-breaking Clinical Trial Presentations at the American Heart Association Scientific Sessions

Recent Headlines from the Late-breaking Clinical Trial Presentations at the American Heart Association Scientific Sessions -

REDUCE-IT – a Landmark Cardiovascular Outcomes Study of an Omega-3 Fatty Acid

 

By Kevin C Maki, PhD and Mary R Dicklin, PhD

 The primary results from the Reduction of Cardiovascular Events with Eicosapentaenoic Acid (EPA) – Intervention Trial (REDUCE-IT) were recently presented at the late-breaking clinical trial sessions of the American Heart Association meeting in Chicago, IL and simultaneously published in the New England Journal of Medicine.1,2  These results followed the topline result announced last month by Amarin, the maker of Vascepa® (icosapent ethyl), indicating an ~25% relative risk reduction in the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularization or unstable angina.3

 REDUCE-IT was a multicenter, randomized, double-blind trial that examined the effects of a high dosage of 4 g/d Vascepa providing ~3700 mg EPA vs. placebo on cardiovascular outcomes in 8179 statin-treated adults at high cardiovascular risk, followed for a median of 4.9 y.1  At entry, participants had an elevated fasting triglyceride (TG) level (median 216 mg/dL) and well-controlled low-density lipoprotein cholesterol (LDL-C; median of 75 mg/dL).  The primary endpoint occurred in 17.2% of patients on Vascepa vs. 22.0% of patients on placebo (hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.68 to 0.83, p < 0.001).  The key secondary endpoint, which was a composite of cardiovascular death, nonfatal MI or nonfatal stroke, occurred in 11.2% of patients on Vascepa vs. 14.8% of patients on placebo (HR 0.74, 95% CI 0.65 to 0.83, p < 0.001).  The rates of all of the individual and composite endpoints (except for death from any cause) were all significantly lower with Vascepa than with placebo.  The overall rates of adverse events during the trial, and the rates of serious adverse events leading to discontinuation, were not significantly different between Vascepa and placebo groups.

A notable finding in REDUCE-IT was a 20% lower rate of cardiovascular death (p = 0.03).1  Our group previously conducted a meta-analysis of 14 randomized controlled trials that investigated the effects of omega-3 fatty acids on cardiac death, and found an 8% lower risk with omega-3 supplementation vs. controls.4  The effect was much larger (~29%) in studies that tested dosages >1 g/d EPA + docosahexaenoic acid (DHA).  Although REDUCE-IT did not include a coronary heart disease (CHD) death endpoint, the publication did include enough information to perform a rough calculation of it based on fatal MI, sudden cardiac death (SCD) and heart failure death.1  There were numerically lower incidence rates for both fatal MI and SCD in REDUCE-IT, but death from heart failure did not differ in the treatment arms, which suggests that the benefit to cardiovascular death was driven by fatal MI, SCD and fatal stroke, but not heart failure death.  To assess the possibility for detecting a benefit for fatal CHD with omega-3 fatty acids, we added our estimate from REDUCE-IT, to the results from a recent meta-analysis conducted by Aung et al.,5 along with data from A Study of Cardiovascular Events in Diabetes (ASCEND),6 and the recently published Vitamin D and Omega-3 Trial (VITAL).7  Doing this demonstrated a statistically significant reduction in fatal CHD with omega-3 fatty acids (details are below).

  • Aung meta-analysis5: 1301 of 39,017 participants for omega-3 and 1394 of 38,900 participants for control;
  • ASCEND6: 100 of 7740 participants for omega-3 and 127 of 7740 participants for control;
  • VITAL7: 37 of 12,933 participants for omega-3 and 49 of 12,938 participants for control;
  • REDUCE-IT (fatal MI + SCD)1: 74 of 4089 participants for omega-3 and 110 of 4090 participants for control;
  • When combined, this shows that CHD death occurred in 2.37% of 63,779 participants receiving omega-3 interventions and 2.64% of 63,668 participants in control conditions; the relative risk is 0.901 (95% CI 0.841 to 0.965, p = 0.003).

The result is also statistically significant without inclusion of the REDUCE-IT findings (relative risk 0.914, 95% CI 0.852 to 0.981, p = 0.013).  The robust results from REDUCE-IT, which included reductions in stroke as well as fatal and non-fatal CHD, suggest that low dosage in many of the prior studies was the reason for failure to demonstrate clear differences between the omega-3 and control groups in cardiovascular event rates.  Whether EPA is superior to DHA for risk reduction remains to be determined, and the results from the ongoing Outcomes Study to Assess Statin Residual Risk Reduction with Epanova® in High Risk Patients with Hypertriglyceridemia (STRENGTH), which are expected in 2019 or 2020, should provide information relevant to assessing this question.8  Epanova provides EPA + DHA in carboxylic acid (free fatty acid) form.

Some experts expressed surprise with the results from REDUCE-IT, because of the numerous unfavorable interpretations of results from other recently published trials and meta-analyses of the effects of omega-3 fatty acids on cardiovascular outcomes.5,6  While we agree that the magnitude of effect in REDUCE-IT, i.e., 25% reduction in risk, was somewhat larger than expected, as we previously expressed, in our opinion, the failure to show benefit in some of those previous studies was due to study design issues.9  Many of the prior studies tested low dosages (most administered just 1 g/d Omacor®/Lovaza® providing ~840 mg EPA + DHA), and they failed to examine the intervention in subjects with hypertriglyceridemia who would be expected to benefit most from a TG-lowering intervention.9  In another meta-analysis, our group found that medications that substantially lower TG (i.e., fibrates, niacin, omega-3 fatty acids) appeared to reduce cardiovascular disease risk in those with elevated TG, especially if accompanied by low high-density lipoprotein cholesterol (HDL-C) levels.10,11  The results from REDUCE-IT confirmed the larger benefit in those with elevated TG plus low HDL-C, with a reduction in the primary outcome of 38% in those with TG ≥200 mg/dL plus HDL-C ≤35 mg/dL, and 21% in those without this combination (p = 0.04 for interaction).

The REDUCE-IT authors suggested that at least some of the reduced risk of ischemic events may be explained by metabolic effects other than reduced TG levels.  This possibility is supported by the finding that the effect of the drug on primary and key secondary outcomes did not differ among those with and without achieved TG <150 mg/dL at one year.  There are several potential mechanisms through which EPA could lower risk beyond TG lowering, including, among others, reductions in inflammation, antiplatelet effects and plaque stabilization.  There was a statistically significant (p < 0.001) difference in high-sensitivity C-reactive protein (hs-CRP) response of 0.4 to 0.9 mg/L (21-40% depending on how calculated and timepoint) between the treatment arms favoring the active treatment group.1  Thus, it is possible, and in our view likely, that anti-inflammatory effects may have contributed to the observed benefits.

There have been concerns raised regarding some of the laboratory results in the trial.  For example, the use of the mineral oil placebo was problematic in that it was associated with increases in TG, LDL-C and non-HDL-C of 2.2%, 10.9%, and 10.4%, respectively at year 1, and apolipoprotein B and hs-CRP of 7.8% and 32.3%, respectively at 2 years.1,2  While not ideal, it is important to compare this to other clinical trials of prescription lipid-altering medications.  For example, among subjects taking placebo in the ODYSSEY Outcomes trial, there was an increase of approximately 12% in LDL-C during the treatment period (92 mg/dL to 103 mg/dL).12  Thus, it appears very unlikely that an adverse effect of the mineral oil placebo can explain more than a small fraction of the observed benefit.  In the Japan EPA Lipid Intervention Study (JELIS),13 a similar drug (1.8 g/d EPA from ethyl esters) reduced the primary cardiovascular endpoint by 19% compared with a no treatment control (not placebo).  The concordance in results between the trials provides compelling evidence that the benefit in REDUCE-IT is not artifactual.

Overall, it is our opinion that the results from REDUCE-IT are an important answer to the question of whether omega-3 fatty acids (EPA alone as icosapent ethyl in this instance) reduce cardiovascular risk when administered at a sufficiently high dosage to subjects with elevated TG who are at high cardiovascular risk.  This is unequivocally good news for patients and has been long-awaited given the large number of trials of low-dosage omega-3 fatty acids that had failed to produce clear evidence of cardiovascular benefit.  Additional trials are warranted to determine whether higher dosages of omega-3 fatty acids will also produce cardiovascular benefits in other population subgroups.

References:

  1. Bhatt DL, Steg G, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2018; Epub ahead of print.

 

  1. Kastelein JJP, Stroes ESG. FISHing for the miracle of eicosapentaenoic acid. N Engl J Med. 2018; Epub ahead of print.

 

  1. Amarin Corporation. REDUCE-IT cardiovascular outcomes study of VASCEPA® (icosapent ethyl) capsules met primary endpoint. September 24, 2018. Available at https://investor.amarincorp.com/news-releases/news-release-details/reduce-ittm-cardiovascular-outcomes-study-vascepar-icosapent.

 

  1. Maki KC, Palacios OM, Bell M, Toth PP. Use of supplemental long-chain omega-3 fatty acids and risk for cardiac death: an updated meta-analysis and review of research gaps. J Clin Lipidol. 2018;11:1152-1160.

 

  1. Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: meta-analysis of 10 trials involving 77917 individuals. JAMA Cardiol. 2018;3:225-234.

 

  1. ASCEND Study Collaborative Group. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018; Epub ahead of print.

 

  1. Manson JE, Cook NR, Lee IM, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 2018; Epub ahead of print.

 

  1. Nicholls SJ, Lincoff AM, Bash D, et al. Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: rationale and design of the STRENGTH trial. Clin Cardiol. 2018;41:1281-1288.

 

  1. Maki KC, Dicklin MR. Omega-3 fatty acid supplementation and cardiovascular disease risk: glass half full or time to nail the coffin shut? Nutrients. 2018;10(7).

 

  1. Maki JC, Guyton JR, Orringer CE, et al. Triglyceride-lowering therapies reduce cardiovascular disease event risk in subjects with hypertriglyceridemia. J Clin Lipidol. 2016;10:905-914.

 

  1. Maki KC, Dicklin MR. Do triglyceride-lowering drugs decrease risk of cardiovascular disease? Curr Opin Lipidol. 2017;28:374-379.

 

  1. Schwarz GG, Steg G, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018; Epub ahead of print.

 

  1. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomized open-label, blinded endpoint analysis. Lancet. 2007;369:1090-1098.
Photo by Martin Brosy

Results from A Study of Cardiovascular Events in Diabetes (ASCEND): Taking a Closer Look at the Potential Benefit of Omega-3 Fatty Acids for Preventing Cardiac Death

Results from A Study of Cardiovascular Events in Diabetes (ASCEND): Taking a Closer Look at the Potential Benefit of Omega-3 Fatty Acids for Preventing Cardiac Death

By Kevin C Maki, PhD; Mary R Dicklin, PhD

 

Results from A Study of Cardiovascular Events in Diabetes (ASCEND) were recently presented at the European Society of Cardiology (ESC) Congress 2018 held in Munich, Germany, along with their simultaneous publication in the New England Journal of Medicine.1,2  ASCEND was designed to evaluate whether daily aspirin safely prevented cardiovascular disease (CVD) and cancer in patients with diabetes, but without known CVD.3  The study also assessed whether supplementation with 1 g/d omega-3 fatty acids prevented CVD.  Persons with diabetes (n = 15,480) were randomly assigned to receive 100 mg/d aspirin or placebo and, in a factorial design, 1 g/d omega-3 fatty acid capsules, containing 460 mg eicosapentaenoic acid (EPA) and 380 mg docosahexaenoic acid (DHA), or placebo (olive oil).  The primary outcome was a first serious vascular event, which was defined as a composite of nonfatal myocardial infarction or stroke (excluding confirmed intracranial hemorrhage), transient ischemic attack, or vascular death.  The secondary outcome was a composite of any serious vascular event or any arterial revascularization procedure. 

 

The results for the omega-3 fatty acid portion of the trial showed no benefit from omega-3 vs. placebo for the primary or secondary composite outcomes.  During a mean follow-up of 7.4 years, a serious vascular event occurred in 8.9% and 9.2% of patients in the omega-3 and placebo groups, respectively, with a rate ratio of 0.97, 95% confidence interval (CI) 0.87 to 1.08, p = 0.55.  The composite outcome of any serious vascular event or revascularization occurred in 11.4% and 11.5% of patients in the omega-3 and placebo groups, respectively, with a rate ratio of 1.00, 95% CI 0.91 to 1.09.  The lack of a significant benefit of omega-3 fatty acids on the pre-specified primary outcome in ASCEND was consistent with results from recent meta-analyses of randomized controlled trials (RCTs) of long-chain omega-3 polyunsaturated fatty acids (compared to control or no treatment) on coronary heart disease (CHD) events.4  In a meta-analysis of 10 RCTs (n = 77,917) Aung et al. reported a risk ratio (95% CI) for a CHD event of 0.96 (0.90 to 1.01).5  Similarly, in a meta-analysis of 18 RCTs (n = 93,633) Alexander et al. reported a risk ratio of 0.94 (0.85 to 1.06).6  Abdelhamid et al. reported a risk ratio of 0.93 (0.88 to 0.97) in a meta-analysis of 28 RCTs (n = 84,301).7

 

Although the balance of the evidence from the RCTs conducted to date is supportive of the conclusion that omega-3 long-chain polyunsaturated fatty acid supplementation does not reduce risk for CHD events, there is promising evidence to suggest that omega-3 fatty acids may be beneficial for preventing fatal CHD or cardiac death.4,8  A meta-analysis of the effects of omega-3 fatty acids on cardiac death (defined as deaths from CHD, cardiac arrhythmia or heart failure) in 14 RCTs (n = 71,899) showed a risk ratio of 0.92 (0.86 to 0.98), p = 0.015.8  Aung et al. also reported a marginally significant reduction in CHD death 0.93 (0.85-1.00).5  In ASCEND, there was a near-significant difference in coronary deaths (incidence rate ratio = 0.79, 95% CI 0.61 to 1.02).1  In addition, there were significantly fewer vascular deaths (which represented 28% of all deaths) in the fatty acid group than in the placebo group (incidence rate ratio = 0.82, 95% CI 0.68 to 0.98).  Vascular deaths included coronary, sudden, stroke, and pulmonary embolism mortality. 

 

The ASCEND investigators suggested the possibility that if their results were to be combined with the studies reported in the meta-analysis by Aung et al., that a small benefit for fatal CHD might be detected.1,5  To assess this possibility, we have added the events reported in ASCEND to the events reported by Aung et al., and there was, in fact, a significant reduction in CHD/coronary death.

 

CHD deaths were as follows:

  • Aung meta-analysis5: 1301 of 39017 participants for omega-3 and 1394 of 38900 participants for control
  • ASCEND1: 100 of 7740 participants for omega-3 and 127 of 7740 participants for control
  • When combined, this is 3.00% of 46757 participants for omega-3 and 3.26% of 46640 participants for control
  • The relative risk is 0.919 (95% CI 0.855 to 0.987, p = 0.021)

 

Commentary

Although it is important to not over-interpret findings from post-hoc subset analyses, these results show promise for the prevention of cardiac death with omega-3 fatty acid supplementation through mechanisms that we outlined in our recent editorial comment in Nutrients.4  Unfortunately, the dosages used in most RCTs of omega-3 fatty acids conducted to date have been small (most employed 1 g/d Omacor/Lovaza, which contains 840 mg of EPA + DHA).  Pooled results from observational studies with omega-3 biomarker measurements suggest that each 1-standard deviation (SD) increase in omega-3 status is associated with a 12-16% reduction in risk for CHD death.9  Based on the same observational study dataset, Harris et al. estimated that a 1-SD increase in omega-3 index (erythrocyte fatty acid EPA + DHA content), or 2.1% from the 10 cohorts included in the analysis, was associated with a 15% (95% CI 9% to 20%) reduction in risk for fatal CHD.10

 

A subset of 152 of the ASCEND participants had omega-3 index measurements completed.  There was no material change in the placebo group (6.6% at baseline and 6.5% at follow-up), whereas the index increased from 7.1% to 9.1% in the omega-3 fatty acid group, resulting in a net difference of 2.1% in the change from baseline, and a difference between groups of 2.6% at the end of the trial.  If the Harris et al. estimate of a 15% reduction in fatal CHD risk per 2.1% (1-SD) omega-3 index difference is applied to the ASCEND data, the predicted risk reduction would be 15%, or 18% if the difference between groups during follow-up of 2.6% (1.24-SDs) is used.10  These estimates are close to the observed difference of 21% in coronary death. 

 

At lower dosages, it is our opinion that there is no compelling evidence to suggest benefits regarding non-fatal myocardial infarction or stroke, but that there is promising evidence for prevention of cardiac death.  Of the three large-scale trials that have been recently completed or are underway, including the Vitamin D and Omega-3 Trial (VITAL),11 the Outcomes Study to Assess Statin Residual Risk Reduction with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia (STRENGTH)12 and the Reduction of Cardiovascular Events with EPA – Intervention Trial (REDUCE-IT),13 only the latter two trials are using a higher EPA+DHA dosage (≥3000 mg/d).  Future investigation should focus on higher dosages than have generally been employed to date.

 

Our view is that the potential for omega-3 fatty acid supplementation to reduce cardiac death clearly deserves additional study.  Further details about why we hold this view may be found in our recent commentary in Nutrients.4  Also, we agree with the recent recommendation from the American Heart Association that it is reasonable to consider an omega-3 fatty acid supplement for patients with atherosclerotic CVD or heart failure.  The message to patients can be as follows:

  1. There is little or no risk associated with taking an omega-3 fatty acid (EPA + DHA) supplementation;
  2. The available evidence does not support a benefit of EPA + DHA supplements for reducing risk of heart attack or stroke;
  3. However, if a heart attack or heart failure should occur, those who take an omega-3 supplement might be less likely to die as a result.

 

References:

 

  1. The ASCEND Study Collaborative Group. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018 [Epub ahead of print].

 

  1. The ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med. 2018 [Epub ahead of print].

 

  1. Bowman L, Mafham M, Stevens W, et al. ASCEND: A study of cardiovascular events in diabetes: characteristics of a randomized trial of aspirin and of omega-3 fatty acid supplementation in 15,480 people with diabetes. Am Heart J. 2018;198:135-144.

 

  1. Maki KC, Dicklin MR. Omega-3 fatty acid supplementation and cardiovascular disease risk: glass half full or time to nail the coffin shut? Nutrients. 2018;10:864.

 

  1. Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: Meta-analysis of 10 trials involving 77,917 individuals. JAMA Cardiol. 2018;3:224-234.

 

  1. Alexander DD, Miller PE, Van Elswyk ME, et al. A meta-analysis of randomized controlled trials and prospective cohort studies of eicosapentaenoic and docosahexaenoic long-chain omega-3 fatty acids and coronary heart disease risk. Mayo Clin Proc. 2017;29:15-29.

 

  1. Abdelhamid AS, Brown TJ, Brainard JS, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2018;7:CD003177.

 

  1. Maki KC, Palacios OM, Bell M, Toth PP. Use of supplemental long-chain omega-3 fatty acids and risk for cardiac death: An updated meta-analysis and review of research gaps. J Clin Lipidol. 2017;11:1152-1160.

 

  1. Del Gobbo LC, Imamura F, Aslibekyan S, et al. n-3 polyunsaturated fatty acid biomarkers and coronary heart disease: pooling project of 19 cohort studies. JAMA Intern Med. 2016;176:1155-1166.

 

  1. Harris WS, Del Gobbo L, Tintle NL. The omega-3 index and relative risk for coronary heart disease mortality: estimation from 10 cohort studies. Atherosclerosis. 2017;262:51-54.

 

  1. Manson JE, Bassuk SS, Lee IM, et al. The Vitamin D and Omega-3 Trial (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials. 2012;33:159-171.

 

  1. NIH. U.S. National Library of Medicine. ClinicalTrials.gov. Outcomes study to assess statin residual risk reduction with Epanova in high CV risk patients with hypertriglyceridemia (STRENGTH). NCT02104817. https://clinicaltrials.gov.ct2/show/NCT02104817.

 

  1. Bhatt DL, Steg PG, Brinton EA, et al. Rationale and design of REDUCE-IT: Reduction of cardiovascular events with icosapent ethyl-intervention trial. Clin Cardiol. 2017;40:138-148.

 

Photo by Percy Pham

Differential Effects of n-3 and n-6 Fatty Acids on Carotid Plaque and Its Progression: Analyses from The Multi-Ethnic Study of Atherosclerosis

Differential Effects of n-3 and n-6 Fatty Acids on Carotid Plaque and Its Progression: Analyses from The Multi-Ethnic Study of Atherosclerosis

By Kristen N Smith, PhD, RD, LD; Mary R Dicklin, PhD; Kevin C Maki, PhD, CLS, FNLA

 Background:

The process of atherosclerotic development is multifactorial involving inflammation, endothelial activation, oxidative stress and lipid accumulation in the arterial wall resulting in plaque accretion and vessel occlusion.1 Data have shown that atherogenesis can occur as early as adolescence2 and support the need for the identification and control of modifiable risk factors.  Long chain omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) have been hypothesized to have antiatherogenic properties, yet the available evidence is inconsistent and no large multiethnic studies have examined n-3 and n-6 levels in plasma in relation to subclinical atherosclerosis outcomes.

Overall, n-3 PUFAs (including plant-derived alpha-linolenic acid [ALA] and fish oil eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) have been considered cardioprotective and their plasma concentrations inversely associated with inflammation and endothelial activation.3-8 Cohort studies have shown n-3 PUFAs to be associated with lower risk of cardiovascular outcomes.9,10 However, null results in recent meta-analyses and randomized controlled trials11-13 have raised questions regarding the benefits associated with n-3 FAs.

Compared to n-3 PUFAs, n-6 PUFAs have not been studied as thoroughly, but have been suggested by some to be proinflammatory and proatherogenic.14 This impression of n-6 PUFAs likely stemmed from the observation that the essential n-6 PUFA, linoleic acid (LA) can be converted to arachidonic acid (AA) – which is a substrate for eicosanoid lipid mediators that promote vascular disease.14,15 More recently this perception has been changing16 and results from observational studies suggest that LA and AA may both have cardiovascular benefits.6,17-19 Conversely, n-6 PUFAs such as gamma-linolenic acid and dihomo-gamma-linolenic acid (mainly created through de novo synthesis from LA) have been associated with inflammation and endothelial activation,6 although researchers are unsure whether higher levels have any impact on atherosclerosis and no large prospective cohort studies have investigated plasma n-6 PUFAs and subclinical measures of atherosclerosis.

This study of participants without apparent cardiovascular disease at baseline examined “whether objectively measured plasma levels of n-3 or n-6 PUFAs were associated with the presence of carotid plaque or occurrence of plaque progression during a median 9.5-year study period, and whether race/ethnicity modified any observed associations.”1

 Methods:

The MESA cohort was gathered from six regions in the United States: Forsyth County, NC; Northern Manhattan and the Bronx, NY; Baltimore City and Baltimore County, MD; St. Paul, MN; Chicago and the village of Maywood, IL; and Los Angeles County, CA. This cohort consisted of men and women of diverse backgrounds between the ages of 45 and 84 years at baseline, who were free from clinical cardiovascular disease. The present investigation included 3327 MESA participants and assessed whether plasma n-3 or n-6 levels were associated with the presence of carotid plaque or occurrence of plaque progression during a median 9.5-year study period.

Fasting samples of blood and plasma were taken throughout the study period and B-mode carotid ultrasonography was conducted at Exam 1 (2000-2002) and Exam 5 (2010-2012) to evaluate carotid artery intima-media thickness and plaque.

Results:

Baseline assessments (stratified by presence of plaque) helped to identify a profile of people less likely to have carotid plaque:

  • Lower mean age (p<0.001)
  • More likely to be women (p=0.003)
  • More likely to have never smoked (p<0.001)
  • Lower mean systolic blood pressure (p<0.001)
  • Less likely to have diabetes mellitus (p<0.001)
  • Lower levels of total cholesterol (p<0.001)
  • Greater levels of plasma LA (p<0.001)
  • Greater levels of plasma DHA (p=0.03)

Profiles were also created of subjects who did not experience plaque progression over the course of the study. This group of individuals had the following characteristics:

  • Lower mean age (p<0.001)
  • Lower body mass index (p=0.016)
  • Lower systolic blood pressure (p<0.001)
  • Lower levels of total cholesterol (p=0.04)
  • Fewer current and former smokers (p<0.001)
  • Fewer individuals taking medication(s) for hypertension (p<0.001)
  • Fewer individuals taking medication(s) for lipids (p<0.001)
  • Greater levels of high-density lipoprotein cholesterol (p=0.002)
  • Greater levels of plasma LA (p=0.003)
  • Greater levels of plasma DHA (p=0.005)

Assessment of quartiles of plasma n-3 and n-6 PUFA concentrations found that subjects in the second quartile of n-3 ALA had an 11% greater risk of having plaque than the quartile 1 referent (p=0.02) but there were no noted relationships for the third and fourth quartiles vs. the referent for the presence or absence of plaque. Participants within the fourth DHA quartile had a 9% lower risk of having carotid plaque compared to the referent (p<0.05), and a 12% lower risk of carotid plaque progression than the referent (p=0.002). There were no significant differences between n-6 PUFA quartiles (2nd through 4th vs. referent) for carotid plaque progression.

At baseline, participants in the top quartile of the n-3/n-6 ratio were at a significantly lower risk of for having carotid plaque (p=0.03) and those in the highest quartiles of EPA+DHA and total n-3 PUFAs were at reduced risk for plaque progression (p=0.01 and p=0.02, respectively). There were no significant relationships between total n-6 PUFAs and either the presence or progression of carotid plaque.

Interaction analysis did not detect a modifying effect of race/ethnicity on associations between PUFAs and baseline carotid plaque or plaque progression.

 Comment:

Overall, these results support an association between plasma levels of n-3 PUFAs, particularly DHA, with lower prevalence and risk for progression of carotid plaque.  No consistent positive or inverse associations were found for n-6 PUFAs and carotid plaque presence or progression. The results of this cohort investigation provide evidence for the ongoing recommendation to incorporate n-3 PUFAs into the diet for preventing or delaying atherogenesis. The lack of significant associations for n-6 PUFAs with plaque presence or progression suggest neither pro- nor anti-atherogenic properties for these fatty acids.

 

References:

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