Replies to post #195953 on Amarin Corp Plc (AMRN)

[ziploc_1]

M....on 9/17/18 you wrote this..."You know, it’s not too late to hedge a bit, or be less “all-in.” You have a lot more experience than me in most things, but not this. They will find what they are dredging for soon, and when they announce the failure with some mediocre positive in a weird subgroup not pre-specified, I won’t say a single word on here. Because then the counter-argument won’t matter to me anymore. And that’s just about the only reason I post.
Actually with that, I’ve said enough."

"If results are bad, I WON'T be back. If they’re good, I’ll come congratulate you all."
...NOW, CONTRARY TO YOUR PROMISE, you're BACK AGAIN WITH A NEW NAME!

[bidmark]

Supplement Boy!

[rafunrafun]

as it is very easy to move the needle of that ratio in EPA's favor by eating a lot of fish, or taking a cheap fish oil supplement with a high percentage of EPA in it.

Anyone sees any similarities? (Don't miss the very bottom)

Why the JELIS study results will not repeat in R-IT.

Almost 70% of subjects in JELIS were women. I've been looking into how n-3 and EPA dosing in particular may give a greater advantage to women than men, and I've been having good success finding that it probably does, like:

Quote:
A recent study conducted with women in the Nurses’ Health Study10 reported an inverse association between fish intake and omega-3 fatty acids and CHD death. Compared with women who rarely ate fish (less than once per month), the risk for CHD death was 21%, 29%, 31%, and 34% lower for fish consumption 1 to 3 times per month, once per week, 2 to 4 times per week, and >5 times per week, respectively (P for trend=0.001).


That's pretty good stuff right there. Higher rates than seen in studies with predominantly male subjects.

So that's a real potential confounder to JELIS data. The inverse number of male:female will likely be represented in R-IT, with some 2/3rds or more being male.

Then there is the fact that subjects in JELIS had quite high baseline LDL-C levels. They initiated low-dose statin at the same time as initiating EPA 1.8g/d. They did not take low dose aspirin. So, the risk benefit of high dose statin and low dose aspirin was *absent*. There was "room to work," so to speak, for EPA dosing.

Luckily they did not get 4.0g/d of EPA, as that might have had an adverse effect too, counteracting the positive :)

Then there is the fact that 100% of JELIS subjects were Japanese, and may have a genetic predisposition to greater utilization of n-3 fatty acids:

Quote:
It is possible to assess omega-3 status via analysis of erythrocyte fatty acids, a measurement that reflects longer-term intakes over approximately the previous 120 days [18,19]. The “omega-3 index” proposed by Harris and von Schacky reflects the content of EPA plus DHA in erythrocyte membranes expressed as a percentage of total erythrocyte fatty acids [20,21]. This index can be used as a surrogate for assessing tissue levels of EPA plus DHA [16,22,23]. EPA and DHA typically comprise about 3%–5% of erythrocyte fatty acids in Western populations with low fish intakes. In Japan, where fish consumption is high, erythrocyte EPA and DHA levels are about twice those of Western populations.


plus:

Quote:
Further RBC membrane omega-3 fatty acid composition is more biologically stable than plasma concentrations,11 and has been shown to be highly correlated with omega-3 fatty acid concentrations in tissues such as the heart.


plus:

Quote:
There is a wide variation in omega-3 blood levels achieved between individuals in response to a given dose of an omega-3 supplement. The individual variation in blood omega-3 levels achieved in response to a fixed daily dose helps to explain why some individuals may obtain CVD protection benefit while others do not due to failure to achieve a therapeutic threshold. Recent development of a population range in a United States population helps to provide clinical guidance since population omega-3 blood level ranges may vary due to environmental and genetic reasons.


equals, hmm... Maybe all those generation of fish consumption led to a genetic selectivity to utilize EPA/DHA.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176556/

Also as evidence (these were all done in "Western" and inlander populations):

Quote:
Some studies have not reported a beneficial association of fish consumption and CHD mortality. In the Health Professionals’ Follow-up Study,11 no significant association was observed between fish intake (and omega-3 fatty acids) and risk of any CHD (ie, fatal coronary disease including sudden death, nonfatal MI, coronary artery bypass grafting, or angioplasty). Likewise, the US Physicians’ Health Study did not show an association between fish consumption (or omega-3 fatty acid intake) and reduced risk of total MI, nonsudden cardiac death, or total cardiovascular mortality.12 In contrast, however, fish consumption was related to a reduced risk of total mortality.

The lack of an association between fish intake and CHD incidence and mortality also was reported from an analysis of the Seven Countries data and the EURAMIC (European Multicenter Case-Control Study on Antioxidants, Myocardial Infarction and Breast Cancer) Study.13,14 In the Seven Countries Study, although an inverse association between fish consumption and 25-year mortality from CHD across several populations was observed,13 when the confounding effects of saturated fatty acids, flavonoids, and smoking were considered, the association was not significant. In the EURAMIC Study, a large international case-control study, no evidence of a protective effect of adipose tissue DHA (a measure of long-term fish consumption) on the risk of developing MI was seen.


Whereas Japanese that live in Western countries have higher risk--due to deviation from native diet (imo):

Quote:
In a study of Japanese living in Japan or Brazil, Mizushima et al9 reported a dose-response relationship between the frequency of weekly fish intake and reduced CVD risk factors (eg, obesity, hypertension, glycohemoglobin, ST-T segment change on the ECG).


So of course returning to that native diet via EPA supp helps THEM. Will it help Westerners? Even the JELIS study cautions against over-interpreting its results to Western counterparts:

Quote:
The beneficial effects of EPA could have stemmed from many biological effects that lead to the attenuation of thrombosis, inflammation, and arrhythmia in addition to a reduction of triglycerides. Overall, this study shows that EPA, at a dose of 1800 mg per day, is a very promising regimen for prevention of major coronary events, especially since EPA seems to act through several biological mechanisms. Because our population was exclusively Japanese, we cannot generalise our results to other populations. We need to investigate whether EPA is effective for prevention of major coronary events in hypercholesterolaemic patients without or with coronary artery disease in other countries.


Yet, that doesn't stop AMRN longs, of course..

Lastly, there was no blind and no propensity to seek out treatments other than the low dose statin control group patients were given. The placebo group for R-IT is not the same. They are on statins at entry. Diabetics with high baseline trigs (and especially who are stented) routinely get lipid panels done every 3-4 months:

https://www.diabetesdaily.com/forum/type-2-diabetes/47308-how-often-should-diabetic-get-lipid-panel-done/

As soon as they see their already high trigs (>200 for 50% of p group, and >300-350 for who knows how many; 499 upper limit) go up a little or remain unchanged, they will know what group they are in.

1,612 events from 8,175 subjects, split 806/806 in a p=1.0 scenario means every 10 or 20 events counts a LOT. Of the 2,000+ p group subjects with trigs >200, how many have trigs >300? Maybe 1,000 of them? How many of these will contribute to those 800-ish events that are so important? And what happens if they switch to fenofibrate once they realize they are on placebo? ACCORD data suggests that high trig subjects can benefit massively from feno...


In summary:

-unstable angina only significant component of MACE in JELIS (though others were trending positively). This soft endpoint is tested more stringently in R-IT
-almost 70% of JELIS were women; most of R-IT pop will be men. Some studies have shown PUFAs may benefit women more than men.
-genetic differences exist between Japanese and Westerners and their ability to utilize EPA/DHA. Because it may benefit Japanese (or especially Japanese women), does not de facto imply it will be of benefit to Westerners.
-4g/d of EPA may counteract the possible positive benefits of a higher dose than the 1.8g/d used in JELIS, including: a) a reduction in vit E levels, b) increase in pro-inflammatory markers, c) significant decrease in baseline HDL levels, and d) higher abnormal liver function tests
atvb.ahajournals.org/content/19/7/1681?ijkey=9695aa8662473e341e9a255a264e211cba4f9f1b&keytype2=tf_ipsecsha%3FlinkType%3DABST&journalCode=atvbaha&resid=19%2F7%2F1681
-Subjects in JELIS were on low-dose statin, and many discontinued use part way through study. Statins may compete with n-3, "masking their potential," as one group of cardiologists opined. All R-IT subjects take optimal dose statin.
http://ajcn.nutrition.org/content/74/1/50.long
-Subjects in JELIS were not taking low dose aspirin. Aspirin may also compete with n-3, masking their potential to show benefit. Subjects in R-IT take low dose aspirin.
-less potential LTFU of high risk placebo group patients due to TG count tells in JELIS than in R-IT, as no placebo control in JELIS. Patients that have high trigs and realize they are on placebo may begin taking fenofibrate, potentially reducing their risk of MCE, and confounding results.


Cheers

Then September 24 happened. Oops.

[sts66]

STRENGTH might even read out with higher EPA levels in its active arm subjects than those treated with Vascepa in REDUCE-IT.

And tomorrow I might even find the fountain of youth and go back to hitting my driver 280-300 yards - or the sun might rise in west and set in the east - both have an equal chance of occurring. It's laughable that you think anyone taking 1/2 the amount of EPA in STRENGTH than V provides could end up with a higher EPA level - it's physically impossible unless that patient is also eating oily fish 2-3 times per week - and big portions of it. Hell, that's really not even possible - there's only 0.4 g/100 g of EPA in Atlantic salmon, 0.5g/100 g in sockeye salmon - you'd need to eat > 4 servings of salmon/week to make up that missing 2 g of EPA. Shad have 1 g/100 g, but fishing for them (meaning keeping and eating) is banned in most states because they were overfished to the point of being an endangered species.