16 replies to this topic

[Michael]

All:

Well, this is a massive disappointment.

As some of you will know, I've long thought that the evidence was strongly in favor of the view that alpha-linolenic acid (short-chain, plant-derived omega-3; ALA) is as effective as EPA and DHA (fish oil) at protecting the heart. Unfortunately, while there is lots of evidence on one or the other, there is very little head-to-head comparisong in a single study, and design features in those studies tend to make strong reliance on them unwise.

A couple of years ago, I started seeing refs to the ongoing Alpha Omega Trial, which was designed to be just what is needed: a single, direct trial of outcomes in heart attack patients which was designed to be just what is needed: a single, direct trial of outcomes in heart attack patients (alas, a clinical trial in perfectly healthy people will never happen: it would take decades to run, wouldn't have as strong an economic payoff, and would cost an absurd amount of money) given either EPA+DHA, ALA, both together, or placebo (all delivered in a very low-trans-fat margarine).


Well, the darned thing has just been published, and they got no significant protective effect from ANY of the interventions:

The patients consumed, on average, 18.8 g of margarine per day, which resulted in additional intakes of 226 mg of EPA combined with 150 mg of DHA, 1.9 g of ALA, or both, in the active-treatment groups.* During the follow-up period, a major cardiovascular event occurred in 671 patients (13.9%). Neither EPA–DHA nor ALA reduced this primary end point (hazard ratio with EPA–DHA, 1.01; 95% confidence interval [CI], 0.87 to 1.17; P=0.93; hazard ratio with ALA, 0.91; 95% CI, 0.78 to 1.05; P=0.20). In the prespecified subgroup of women, ALA, as compared with placebo and EPA–DHA alone, was associated with a reduction in the rate of major cardiovascular events that approached significance (hazard ratio, 0.73; 95% CI, 0.51 to 1.03; P=0.07). The rate of adverse events did not differ significantly among the study groups.(1)

Why does this contrast with most previous evidence on the subject? I think it's pretty obviously because of a critical design element of which I had been previously unaware: ALL patients in the trial "were receiving state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy"(1)!

Obviously, when you have patients that are already as well-managed as the medical system can do, using meds that do some of the same things that n3 does to protect the heart, you're going to minimize the benefit. This result is unsurprising; what's surprising is that they designed the thing this way in the first place.

So we learn essentially nothing, except that after you've already gone to the trouble of getting heart patients to take drugs to control their blood pressure, lower their lipids (and in most cases inflammation), and thin their blood, it's not worth the time and expense to ALSO get them to start eating more omega-3 fatty acids.

No, I do not think that this was a Vast Pharmaceutical Industry Conspiracy Against Supplements. Rather, I imagine that this was done because of some kind of misguided "ethical" concern, where they didn't want to "deny" patients the best that we already know we can do for them in order to set them up as guinea pigs for omega-3s. But omega-3s are cheaper, safer, easier to administer, and there is nowhere near the profit motive required for robust funding as their is for patentable drugs (tho' they did get suppport in the form of "Margarine development, production and distribution" from Unilever, who of course makes this kind of product).

What academic and public-health funding and scientists are uniquely equipped to do is to test omega-3s could do on their own, INSTEAD of aggressive pharmaceutical risk factor management -- or, better yet, to set them up AGAINST such a strategy in a fifth arm of the trial (or even a sixth: placebo vs. ALA vs EPA+DHA vs all 3 omegas vs pharma vs. pharma plus one or both omegas).

What a silly waste of money and opportunity.

2 additional findings, suggestive but not robust enough to rely on:

We observed a nonsignificant 9% reduction in the primary end point with ALA supplementation, as compared with placebo and EPA–DHA only, in the total patient population and a 27% reduction, which approached significance, among women. The Kaplan–Meier curves started to diverge after approximately 20 months, especially among women (Figure 4 in the Supplementary Appendix), suggesting that there was a cumulative effect over time. ALA may slow the formation and calcification of atherosclerotic plaque, as suggested by the results of cross-sectional analyses in the National Heart, Lung, and Blood Institute Family Heart Study. Other possible mechanisms of a beneficial effect of ALA on cardiovascular disease are plaque stabilization and antiarrhythmic effects, either directly or through desaturation and elongation of ALA into EPA. It is also possible that this apparent effect was due to the play of chance. Additional trials involving high-risk patients, however, are needed to prove a cardioprotective effect of ALA.

Patients with diabetes who have had a myocardial infarction are particularly prone to ventricular arrhythmias and sudden death. In a post hoc, exploratory analysis of data from these diabetic patients, we found reductions in cardiovascular end points with EPA–DHA, as compared with placebo, that were in line with those shown in the GISSI Prevenzione trial. The strongest effects — reductions of approximately 50% — were the effects on the rates of fatal coronary heart disease and arrhythmia-related events. The rate of arrhythmia-related events was also reduced with ALA as compared with placebo or EPA–DHA only. This finding is supported by the results of a cohort study involving women, in which ALA intake was inversely associated with the risk of sudden death. However, it is important to note that our results with respect to patients with diabetes are only hypothesis-generating and do not permit definitive conclusions to be drawn.((1) op cit)

*(PS: yes, the dosage was plenty (tho' I'd've liked a LITTLE more ALA): evidence from existing clinical trials and epidemiology are pretty clear that there is a threshold effect right around these doses with no additional, dose-dependent benefit beyond them).

Reference
1. n–3 Fatty Acids and Cardiovascular Events after Myocardial Infarction
Daan Kromhout, M.P.H., Ph.D., Erik J. Giltay, M.D., Ph.D., and Johanna M. Geleijnse, Ph.D. for the Alpha Omega Trial Group
New England Journal of Medicine; Online First, August 29, 2010 (10.1056/NEJMoa1003603)
http://www.nejm.org/...6/NEJMoa1003603
No PMID yet

Edited by Michael, 31 August 2010 - 03:42 PM.

[nameless]

Nice analysis, thanks for posting the study.

One thing I noticed and wondered about in some studies, are we sure the dosage is actually 'plenty'?

Epidemiology has shown that approx. 400-500mg or so provides some benefits, but that is from eating actual fish. Absorption rates may differ between those who eat fish for their Omega 3s vs ethyl ester fish oil (mixed studies there, but trend seems to indicate natural trig fish oil > ethyl ester).

So perhaps 1 gram or more of ethyl ester fish oil is needed to equal the 400mg obtained via eating real fish? Has there ever been a study comparing the same exact doses of Omega 3s, one group eating fish, one group taking fish oil?

And is the ALA trend in the above study due to women converting ALA to EPA better than men can?

[mwestbro]

Interestingly, many if not most of the large supplement trials have been confounded by concomitant pharmaceutical treatment. If this matters (and it clearly does) we can throw out a LOT of well known trials.

1. J Nutr. 2008 Jun;138(6):1179-81.

Statin treatment as a confounding factor in human trials with vitamin E.

Violi F, Cangemi R.

Department of Experimental Medicine and Pathology, University of Rome, La
Sapienza, Rome 00161, Italy. francesco.violi@uniroma1.it

Interventional trials with vitamin E have been planned on the assumption that it
could reduce atherosclerotic progression via inhibition of oxidative stress.
These trials have been conducted in patients at risk for or with cardiovascular
disease, but the results have been divergent. The reason for the equivocal
results is still unclear. We have recently demonstrated that in patients with
hypercholesterolemia, the administration of a statin is associated with reduced
urinary isoprostanes, a marker of oxidative stress, and normalization of
circulating levels of vitamin E, indicating that statins enhance the antioxidant
status. Based on these arguments, we reanalyzed the interventional trials with
vitamin E to see if concomitant use of statins could have created a potential
bias. We reviewed 9 interventional trials, each including > 1000 patients. In 5
of the 9 trials, the concomitant use of statins was reported. In the arm
randomized to vitamin E, a concomitant use of statins was reported in at least
one-third of the population. In some trials, the percentage of patients given
statins was > 50%, suggesting that a large part of the follow-up population was
likely useless treated with vitamin E in view of the concomitant antioxidant
effect of statins. Also, the anti-atherosclerotic effect of statins could have
reduced the possibility that a prespecified sample size had an adequate power to
observe a difference between vitamin E and placebo-treated groups. We therefore
suggest that a meta-analysis of trials with vitamin E should be re-done by
excluding patients who concomitantly used statins.


PMID: 18492853 [PubMed - indexed for MEDLINE]

[kismet]

A few incoherent thoughts of mine:
I do wonder if the study was underpowered to detect a more realistic and modest effect? ("For major cardiovascular events, we had a power of 96% to detect a true hazard ratio of 0.75 and a power of 82% to detect a hazard ratio of 0.80.")
Did they cook with those margarines and would it have altered the results?

How does this affect recommendations to take EPA/DHA or ALA for life extensionists if at all? (cronies & ad lib)

Why does this contrast with most previous evidence on the subject? I think it's pretty obviously because of a critical design element of which I had been previously unaware: ALL patients in the trial "were receiving state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy"(1)!

Interestingly this result was at least somewhat predictable after the failure of the OMEGA trial which had shown that well-managed MI patients do not derive benefit from N3 supplementation in the short term (1 year).

No, I do not think that this was a Vast Pharmaceutical Industry Conspiracy Against Supplements. Rather, I imagine that this was done because of some kind of misguided "ethical" concern, where they didn't want to "deny" patients the best that we already know we can do for them in order to set them up as guinea pigs for omega-3s. But omega-3s are cheaper, safer, easier to administer, and there is nowhere near the profit motive required for robust funding as their is for patentable drugs (tho' they did get suppport in the form of "Margarine development, production and distribution" from Unilever, who of course makes this kind of product).


What academic and public-health funding and scientists are uniquely equipped to do is to test omega-3s could do on their own, INSTEAD of aggressive pharmaceutical risk factor management -- or, better yet, to set them up AGAINST such a strategy in a fifth arm of the trial (or even a sixth: placebo vs. ALA vs EPA+DHA vs all 3 omegas vs pharma vs. pharma plus one or both omegas).

Of course your conclusion is entirely reasonable, but I think it is based on a faulty premise. Denying state of the art treatment to patients, even informed patients, is ethically problematic indeed.
Another argument in favour of the chosen design I think is that we *knew* after the GISSI-P that N3 may benefit patients that are *not* well managed. So the Q whether N3 provide added benefits was more important than replicating the older results. And even if N3 proved to be half as good as standard therapy alone but provided no additive benefit the study could be deemed a failure. What good would this result do if in practise most MI patients opted for superior standard therapy? What novel data would this give us? Exploring this hypothesis would have been problematic ethically and financially; very risky. IMHO the funds would be better invested in a primary prevention trial (or part of it; or improving power of this one) instead of more study arms.

Perhaps the study is not even a failure of priorities: it seems the study was initiated before the failure of the OMEGA trial became known. So the "silly waste of money and opportunity" seems like (mostly) bad luck to me.

Exposing informed patients to a dangerous treatment (or in this case: lack of treatment), is only ethical if there are no good alternatives.

The solution to this would have been to to test the N3 intervention among populations that would not have access to state of the art medicine anyway (is this possible at all? isn't it redundant after the GISSI-P?) or test it for a condition w/o good established treatments e.g. primary prevention in the general population.

The upcoming VITAL may provide more definitive and novel data. Of course they will test the interventions in at risk populations, but at least many if not most patients will be unmedicated.

VITAL (VITamin D and OmegA-3 TriaL), Brigham and Women's study
n~20 000, 5years, 2000IU, 1g fish oil (?)
http://www.brighaman...aspx?PageID=508

Btw, am I getting the large RCTs that tested isolated N3 interventions right?
Alpha-Omega trial, OMEGA, DART, DART-2, GISSI-P, JELIS
Upcoming: Vital, GISSI-HF, ORIGIN

2 additional findings, suggestive but not robust enough to rely on:

We observed a nonsignificant 9% reduction in the primary end point with ALA supplementation, as compared with placebo and EPA–DHA only, in the total patient population and a 27% reduction, which approached significance, among women. The Kaplan–Meier curves started to diverge after approximately 20 months, especially among women (Figure 4 in the Supplementary Appendix), suggesting that there was a cumulative effect over time. ALA may slow the formation and calcification of atherosclerotic plaque, as suggested by the results of cross-sectional analyses in the National Heart, Lung, and Blood Institute Family Heart Study. Other possible mechanisms of a beneficial effect of ALA on cardiovascular disease are plaque stabilization and antiarrhythmic effects, either directly or through desaturation and elongation of ALA into EPA. It is also possible that this apparent effect was due to the play of chance. Additional trials involving high-risk patients, however, are needed to prove a cardioprotective effect of ALA.

Reads like poor reasoning to me; anti-calcific effects are well-documented for EPA+DHA and do not *distinguish* ALA. AFAIK same goes for the other effects. This does not seem to be a good biological rationale. It could be any of those effects, but I don't see evidence for either. Do you have a hypothesis?

@ nameless
The epidemiological benefits start if not become maximized at a dose of 200-300mg EPA+DHA (as per the study and see also: "Mozaffarian and Rimm concluded from their meta-analysis of cohort studies and clinical trials that a daily intake of 250 mg of EPA and DHA reduced the risk of fatal coronary heart disease by 36%. There was no additional benefit from higher intakes.") IAC, there was an EPA/DHA+ALA group that showed no effect either.
Though, the Q of bioav. is an interesting one.
If the effect were due to conversion of ALA to EPA, wouldn't you expect the actual EPA group to do better?

Edited by kismet, 01 September 2010 - 06:33 PM.

[nameless]

@ nameless
The epidemiological benefits start if not become maximized at a dose of 200-300mg EPA+DHA (as per the study and see also: "Mozaffarian and Rimm concluded from their meta-analysis of cohort studies and clinical trials that a daily intake of 250 mg of EPA and DHA reduced the risk of fatal coronary heart disease by 36%. There was no additional benefit from higher intakes.") IAC, there was an EPA/DHA+ALA group that showed no effect either.
Though, the Q of bioav. is an interesting one.
If the effect were due to conversion of ALA to EPA, wouldn't you expect the actual EPA group to do better?

Yes, probably, but not if the conversion of ALA to EPA in women ended up in more EPA than the EPA supplemented group.

1.9 g of ALA at a conversion rate of, let's say 30%, = 570mg of EPA, which is over double the amount of EPA used in the study. I've seen varying conversion rates, but women are known to convert ALA to EPA better than men, so it could make some sense as to why women showed a trend in the study, yet it didn't for men.

It also could mean if they included another group in the study using higher does of EPA, it would have shown some benefits.

Or it could be due to some other benefit from ALA outside of the Omega 3 content, or was just a fluke.

[Michael]

are we sure the dosage is actually 'plenty'?

Epidemiology has shown that approx. 400-500mg or so provides some benefits, but that is from eating actual fish. Absorption rates may differ between those who eat fish for their Omega 3s vs ethyl ester fish oil (mixed studies there, but trend seems to indicate natural trig fish oil > ethyl ester).

So perhaps 1 gram or more of ethyl ester fish oil is needed to equal the 400mg obtained via eating real fish? Has there ever been a study comparing the same exact doses of Omega 3s, one group eating fish, one group taking fish oil?

Surely you jest . As to relative bioavailability as a dosing confounder: both Flora/Becel Omega3 Plus (which is actually made by Unilever) and the competing Smart Balance® Omega-3 Buttery Spread use fish oil, not ethyl esters, so there might be some difference -- but (a) as you say, the results of studies of various fish oil formulations don't actually lead to any clear conclusions on the relative bioavailability of the different formulations, (b) the ones that show an effect tend to show them in association with a massive additional fat bolus, which I don't think terribly strong, but some of the others have it with no fat AT ALL, which is silly; what you want to do with ANY n3 source is take it with some fat, and of course that's exactly what taking it with margarine provides; and © I put it to you that the absorption difference even in the pharmacokinetic studies that DO report one is minor.

Happily, thanks to Kismet, I've just been alerted to the OMEGA-Trial(1), which almost seems designed to directly address your concern. They randomized 3,827 similarly aggressively-managed MI patients to "one year treatment with highly purified omega-3-acid ethyl esters-90 [ie, Zodin/Lovaza/Omacor -- the same supplement used in the GISSI trial -- at 460 mg EPA + 380 mg DHA according to TheHeart.org]" vs olive oil "on the rate of sudden cardiac death, total mortality, non-fatal reinfarction, or stroke after myocardial infarction."

Principal investigator Dr Jochen Senges (University of Heidelberg, Germany), as summarized by TheHeart.org, indicated that:

There was no difference in the rate of the primary end point—sudden cardiac death—which occurred in 1.5% of patients in both groups. Nor were there any differences in any secondary end points ... The study was underpowered to show an effect, because of the low rate of sudden cardiac death ... [but] there was no trend toward benefit with omega-3 -- the survival curves "were extremely superimposable" -- so it was unlikely that even an adequately powered study would have demonstrated any advantage.

I am told by one of the investigators that this should be in peer-reviewed publication within the next few weeks.

If you're worried about it, of course, you can just take a triglyceride-format, conventional fish oil pill, and take it with a fat-containing meal, and be done with it. Or you can actually eat fish . (Or, as I've argued, you can take flax oil or even canola, with probably equal or greater benefit and less environmental impact; plus, if you're on CR, you would avoid teh risk of countervailing some of its anti-aging effect (the DHA-Accelerated Aging Hypothesis).

And is the ALA trend in the above study due to women converting ALA to EPA better than men can?

Could be, but evidently from the conversion process itself (on which hypothesis I could take up a whole post ...) not from the resulting EPA itself since (a) EPA per se didn't even show a trend, and (b) they found an ass'n with PLASMA ALA, but NOT EPA or DHA, in the Lyons study, and favorable outcomes; but in general, women not only have lower mortality than men do, but also respond more sensitively to many lifestyle differences. Doesn't much matter from a practical POV, of course: the INTERVENTION is what counts, not the mechanism.

Did they cook with those margarines and would it have altered the results?

An interesting question -- tho' presumably they'd've cooked with ALL of the margarines, an n-3 margarine would presumably be more susceptible to peroxidation. Of course, I find the idea of cooking with margarine repulsive on purely aesthetic grounds, but that's just me ...

How does this affect recommendations to take EPA/DHA or ALA for life extensionists if at all? (cronies & ad lib)

If it means anything at all, it's one more reason to favor ALA over EPA/DHA .

No, I do not think that this was a Vast Pharmaceutical Industry Conspiracy Against Supplements. Rather, I imagine that this was done because of some kind of misguided "ethical" concern ...

Of course your conclusion is entirely reasonable, but I think it is based on a faulty premise. Denying state of the art treatment to patients, even informed patients, is ethically problematic indeed.

Well, I just don't agree. If you want t run a clinical trial to determine something, you need to test it cleanly. And there are certainly people uncomfortable with pharma for any number of reasons, who might well be happy to test out n3 and not be so managed -- although there are fewer of them, recruiting them would be harder, and of course there's the problem of supplement use in controls ...

Another argument in favour of the chosen design I think is that we *knew* after the GISSI-P that N3 may benefit patients that are *not* well managed. So the Q whether N3 provide added benefits was more important than replicating the older results.

That's a question. Another, debated extensively in the medical literature, is the relative merits of ALA vs EPA/DHA. The former has not been tested as much as the latter, and they've never been done properly head-to-head; this would have been a beautiful test to resolve the issue.

The upcoming VITAL may provide more definitive and novel data. Of course they will test the interventions in at risk populations, but at least many if not most patients will be unmedicated.

VITAL (VITamin D and OmegA-3 TriaL), Brigham and Women's study
n~20 000, 5years, 2000IU, 1g fish oil (?)
http://www.brighaman...aspx?PageID=508

Better link to the VITAL trial of vitamin D and omega-3 here. But they're only testing fish oil! And, it's quite likely (as you note above) that most Americans will indeed be getting pharma.

Reference
1. Jochen Senges, Rudolf Schiele, Steffen Schneider, Helmut Gohlke, Martin Gottwik, Gerhard Steinbeck, Roberto Marchioli, Rudolf Sack, Heinrich Worth, Hugo Katus, Tobias Heer, Reinhilde Zimmer, Werner Richter, Frank Diller, Bernhard Rauch, OMEGA Study Group
Randomized Trial of Omega-3 Fatty Acids on Top of Modern Therapy After Acute Myocardial Infarction: The OMEGA-Trial
Presentation Number: 411-6
Presentation Time: Monday, Mar 30, 2009, 10:30 AM -10:42 AM

[nameless]

Principal investigator Dr Jochen Senges (University of Heidelberg, Germany), as summarized by TheHeart.org, indicated that:

There was no difference in the rate of the primary end point—sudden cardiac death—which occurred in 1.5% of patients in both groups. Nor were there any differences in any secondary end points ... The study was underpowered to show an effect, because of the low rate of sudden cardiac death ... [but] there was no trend toward benefit with omega-3 -- the survival curves "were extremely superimposable" -- so it was unlikely that even an adequately powered study would have demonstrated any advantage.

I am told by one of the investigators that this should be in peer-reviewed publication within the next few weeks.

If you're worried about it, of course, you can just take a triglyceride-format, conventional fish oil pill, and take it with a fat-containing meal, and be done with it. Or you can actually eat fish . (Or, as I've argued, you can take flax oil or even canola, with probably equal or greater benefit and less environmental impact; plus, if you're on CR, you would avoid teh risk of countervailing some of its anti-aging effect (the DHA-Accelerated Aging Hypothesis).

Somewhat disappointing results from the Omega-trial, but I guess it does back up the theory that well-managed patients do not receive a benefit from Omega 3s. Although I would have liked to have seen a higher dose used in the same study too, say around 2 grams or so -- a level that should improve triglyceride numbers. Unless there was a part of the study that perhaps did use that amount? But if the patient is on a heavy-dose statin already, there likely wouldn't be much benefit trig-wise anyway.

One thought I had regarding the margarine study, which may be a dumb thought -- but I'll throw it out there anyway -- did the participants increase their intake of breads or other wheaty foods when eating the margarine? Just curious how they consumed it, and if they did in fact increase bread consumption (which I tend to think of when people eat butter/margarine), that could have been a factor -- ie Dr. Davis' anti-wheat theory.

Unlikely, but again, it was something that crossed my mind.

As for myself, I am doing the triglyceride form of fish oil daily, as although I do eat fish once in a while, mercury scares me. And the healthiest types of fish, such as salmon, just happen to be the type of fish I don't like the taste of. I did try flax oil instead, briefly, but it caused some stomach issues/acid reflux. I think it was due to the fact one has to take much more flax than fish oil, to get the equivalent omega 3s, and my belly didn't like that much.

[yoyo]

Could be something else in fish. I'd like to see a metanalysis of fish vs fish oil.

[Michael]

The aforementioned OMEGA Study has now been published, to negative result as noted:

Circulation. 2010 Nov 8. [Epub ahead of print]
OMEGA, a Randomized, Placebo-Controlled Trial to Test the Effect of Highly Purified Omega-3 Fatty Acids on Top of Modern Guideline-Adjusted Therapy After Myocardial Infarction.

Rauch B, Schiele R, Schneider S, Diller F, Victor N, Gohlke H, Gottwik M, Steinbeck G, Del Castillo U, Sack R, Worth H, Katus H, Spitzer W, Sabin G, Senges J; for the OMEGA Study Group.

Institut für Herzinfarktforschung Ludwigshafen an der Universität Heidelberg, Ludwigshafen.
Abstract

Background- There is no randomized, double-blind trial testing the prognostic effect of highly purified omega-3 fatty acids in addition to current guideline-adjusted treatment of acute myocardial infarction. Methods and Results- OMEGA is a randomized, placebo-controlled, double-blind, multicenter trial testing the effects of omega-3-acid ethyl esters-90 (1 g/d for 1 year) on the rate of sudden cardiac death in survivors of acute myocardial infarction, if given in addition to current guideline-adjusted treatment. Secondary end points were total mortality and nonfatal clinical events. Patients (n=3851; female, 25.6%; mean age, 64.0 years) were randomized in 104 German centers 3 to 14 days after acute myocardial infarction from October 2003 until June 2007. Acute coronary angiography was performed in 93.8% and acute percutaneous coronary intervention in 77.8% of all patients. During a follow-up of 365 days, the event rates were (omega and control groups) as follows: sudden cardiac death, 1.5% and 1.5% (P=0.84); total mortality, 4.6% and 3.7% (P=0.18); major adverse cerebrovascular and cardiovascular events, 10.4% and 8.8% (P=0.1); and revascularization in survivors, 27.6% and 29.1% (P=0.34). Conclusions- Guideline-adjusted treatment of acute myocardial infarction results in a low rate of sudden cardiac death and other clinical events within 1 year of follow-up, which could not be shown to be further reduced by the application of omega-3 fatty acids. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00251134.

PMID: 21060071

[kismet]

I said the ORIGIN trial is ongoing, but now it has been completed. As per this article:

The ORIGIN study is an international double-blind study with a 2x2 factorial design. In total, 12 537 patients with cardiovascular disease or at high risk for cardiovascular events who had an impaired fasting glucose, impaired glucose tolerance, or diabetes were randomly assigned to receive insulin glargine, with a target fasting glucose of <95 mg/dL, or standard care; and to receive n-3 fatty acids, containing at least 900 mg of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), or placebo.
...
In the other randomization, which was presented by Dr Jackie Bosch (McMaster University, Hamilton, ON), patients were treated with 1 g of omega-3 fatty acids and compared with patients who received placebo. Despite reductions in triglyceride levels, which were reduced 14.5 g/dL more among the patients who received the omega-3 fatty acids, treatment failed to reduce the risk of cardiovascular outcomes.

The rate of death from cardiovascular causes was 9.1% in patients treated with placebo and 9.3% in patients treated with omega-3 fatty acids, a nonsignificant difference. In addition, there was no significant treatment effect on any of the secondary end points, including a composite of MI, stroke, or death from cardiovascular causes. Deaths from arrhythmias were also unaffected by treatment with omega-3 fatty acids.

http://www.theheart....ipid/Metabolic)

A recent Meta-analysis of trials showed null results BEFORE ORIGIN was published. This is very bad news, but the most important trial for us is still going on. (Primary prevention in the VITAL study)

Implications? Perhaps lower EPA/DHA and prefer ALA.

Edited by kismet, 02 July 2012 - 10:44 AM.

[Snoopy]

You can drill technically as much as you want, but I think you are just digging yourselves into a hole. There are competing variables all over the place.

You need to correctly visualize the whole and form a judgement based on that, in my opinion...

Take this statement for example and you will see where I am coming from:

"myocardial cell membranes become remodeled with advanced age possibly due to stress and oxidative damage, and this remodeling impacts negatively on mitochondrial function which is critical for sustaining energy production in cardiac membranes. The age-related remodeling appears to involve an imbalance between omega-3 and omega-6 fatty acids in these membranes as well as dysfunctional Ca2+ metabolism. The mechanisms of buildup of arterial plaque are related to over-eating, poor eating, overweight, stress, high blood pressure, conditions such as diabetes, immune fatigue and lack of exercise.Chronic inflammation is at the head of the list, and also implicated are tissue glycation, oxidative stress, declining immune functions, and changes in hormone levels.Insulin resistance is also highly implicated in the creation of heart disease risk as well, of course, in diabetes. A vicious cycle ensues for people who are genetically susceptible to insulin resistance when they eat a high glycemic-index diet and are sedentary."

http://www.vincegiul...ngfirewalls.htm

[niner]

I don't get what you're saying, Snoopy. There are lots of reasons for cardiovascular disease. We used to think that fish oil would reduce heart disease risk because it favorably impacts some biomarkers that are known to be relevant to CVD. However, now we are seeing some evidence that fish oil is not helpful for CVD. A plausible explanation is that the increased oxidation is counteracting the improvements in triglycerides and other markers.

No one is saying that fish oil is the only cause of CVD, if that's what you're getting at. If you look at a big-picture endpoint, like total mortality, as they did in the OMEGA study posted by Michael above, the fish oil intervention does not look good either. It's starting to look like rather than being the miracle supplement that improves everything, maybe fish oil needs a re-think. I'm not ready to stop all fish oil, but I sure as hell wouldn't megadose it.

[Hebbeh]

The point I think Snoopy might be trying to make is that CVD is mostly caused by poor diet, lack of exercise, and poor lifestyle choices (couch potato) and fish oil is not going to be the silver bullet to cancel out all those negatives. It's like the obese couples I see at McD's....believing if they get a diet soda with their super sized meal, that the diet soda will cancel all the trans fats out. You have to have the basics (diet, exercise, lifestyle) in place first...then things like fish oil can be additive and beneficial....but all the fish oil in the world is not going to make up for over eating a crappy diet and sitting on the couch. A spade is a spade....in this case, an obese gluttonous coach potato.

[niner]

The point I think Snoopy might be trying to make is that CVD is mostly caused by poor diet, lack of exercise, and poor lifestyle choices (couch potato) and fish oil is not going to be the silver bullet to cancel out all those negatives. It's like the obese couples I see at McD's....believing if they get a diet soda with their super sized meal, that the diet soda will cancel all the trans fats out. You have to have the basics (diet, exercise, lifestyle) in place first...then things like fish oil can be additive and beneficial....but all the fish oil in the world is not going to make up for over eating a crappy diet and sitting on the couch. A spade is a spade....in this case, an obese gluttonous coach potato.

I don't think anyone is promoting fish oil as a silver bullet that lets you get away with murder, lifestyle-wise. It's just that for a long time, we assumed that the beneficial effects on markers would translate into better health outcomes, and it looks like that's not true. At least not for sick people. I don't think that we have any evidence that fish oil improves all-cause mortality in healthy people, which is probably the figure of merit that most of us care about. I agree that we need to have the basics in place, I'm just not so sure that the fish oil will be a net positive even then. For some people, it may be worth some oxidative injury to get a nootropic effect; maybe they could compensate with more antioxidants. For the rest of us, maybe we should think about putting more effort into eliminating omega 6 PUFAs from our diets.

[Carroll]

Who say omega 3 don't protect the heart?
Omega 3 is a best supplement for the heart health.
It controls the cholesterol level, burns fat, loses the unnecessary weight and keeps the heart healthy.

[tham]

These trials have all to be taken with a grain of salt. One can't
conclude any of them to be the "gospel truth" with surefire accuracy

Confounding factors will no doubt be involved, including the design
of the trial itself - this is why you see conflicting results on Medline,
whether drugs, herbs or supplements, every now and then.

One major study says fish oil works well, the next says it is useless.

There's one significant confounding factor which many overlook - compliance.

Each participant is given say two fish oil softgels to take home every day, along
with other supplements like vitamin E as the case may be, or all placebos otherwise.

If he doesn't take any of them, or takes some but throws away others, and he tells
his doctor or whoever is monitoring him that he did, the consequences are obvious.

Or he may follow the instructions faithfully on some days or weeks, but does
the above on others.

Nobody is going to be beside him that he pops each and every supplement (or
drug) into his mouth, moreover at the exact dosage, every day for months, as directed.

However well designed the trial may be, would come to nothing in the end.

Edited by tham, 10 November 2012 - 10:19 PM.

[hanswu]

Published from the Alpha Omega Trial:

Eur Heart J. 2012 Jul;33(13):1582-8. doi: 10.1093/eurheartj/ehr499. Epub 2012 Feb 1.
Effects of n-3 fatty acids on major cardiovascular events in statin users and non-users with a history of myocardial infarction.

Eussen SR, Geleijnse JM, Giltay EJ, Rompelberg CJ, Klungel OH, Kromhout D.

Author information


Abstract


AIMS:

Recent secondary prevention trials have failed to demonstrate a beneficial effect of n-3 fatty acids on cardiovascular outcomes, which may be due to the growing use of statins since the mid-1990s. The aim of the present study was to assess whether statins modify the effects of n-3 fatty acids on major adverse cardiovascular events in patients with a history of myocardial infarction (MI).
METHODS AND RESULTS:

Patients who participated in the Alpha Omega Trial were divided into consistent statin users (n = 3740) and consistent statin non-users (n = 413). In these two groups of patients, the effects of an additional daily amount of 400 mg eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA), 2 g α-linolenic acid (ALA), or both on major cardiovascular events were evaluated. Multivariable Cox's proportional hazard models were used to calculate adjusted hazard rate ratios (HR(adj)). Among the statin users 495 (13%) and among the statin non-users 62 (15%) developed a major cardiovascular event. In statin users, an additional amount of n-3 fatty acids did not reduce cardiovascular events [HR(adj) 1.02; 95% confidence interval (CI): 0.80, 1.31; P = 0.88]. In statin non-users, however, only 9% of those who received EPA-DHA plus ALA experienced an event compared with 18% in the placebo group (HR(adj) 0.46; 95% CI: 0.21, 1.01; P= 0.051).
CONCLUSION:

In patients with a history of MI who are not treated with statins, low-dose supplementation with n-3 fatty acids may reduce major cardiovascular events. This study suggests that statin treatment modifies the effects of n-3 fatty acids on the incidence of major cardiovascular events.

Retrospective, not robust.