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Increase in EPA/AA Ratio Predicts Improvement in Endothelial Function in Purified Eicosapentaenoic Acid-Treated Patients
conclusions
EPA treatment improves endothelial dysfunction in patients with hypertriglyceridemia without evidence of CAD. The change in FMD was associated with the change in EPA/AA ratio alone. These finding suggest that a direct effect of EPA on the endothelium may be the predominant factor ameliorating endothelial function
https://academic.oup.com/eurheartj/article-abstract/40/Supplement_1/ehz746.0810/5597439
Note conclusion RE DPA
The omega-3 fatty acid eicosapentaenoic acid (EPA) is inversely associated with ischemic brain infarcts in elderly patients with atrial fibrillation
https://academic.oup.com/eurheartj/article-abstract/40/Supplement_1/ehz745.0566/5597166?redirectedFrom=fulltext
Thanks for that Gábor- Hilarious
Pleiotropic health benefits of EPA beyond CVD $AMRN
"Protective effects of Eicosapentaenoic acid in adipocyte-breast Cancer cell cross-talk"
https://www.sciencedirect.com/science/article/abs/pii/S0955286319304735
Evaporate results will be a potent new insight / proof point to shared by Amarin reps, Rx will accelerate as a result.
Also makes for a terrific line in consumer focused TV ads
New commercial fishing technology allows fleets to double fishing capacity—and deplete fish stocks faster
https://phys.org/news/2019-09-technology-fleets-fishing-capacityand-deplete.html
For everyone except J.L. Interview with Dr Judith Campisi on aging from stress response causing inflammation (two sources of inflammation) , effects of senescent cells etc
BB, my recommendation is ignore $AMRN until Adcom. Enjoy your life, it’s about to get better
Dr Bhatt paper
https://www.ncbi.nlm.nih.gov/pubmed/31464773/
?Heart Failure prevention using Vascepa. The case for investigation ?
?http://www.natap.org/2019/HIV/j.jchf.2019.04.007.full.pdf?
Mellow, link?
International Society for Nutritional Psychiatry Research Practice Guidelines for Omega-3 Fatty Acids in the Treatment of Major Depressive Disorder.
Guu TW1,2, Mischoulon D3, Sarris J4,5, Hibbeln J6, McNamara RK7, Hamazaki K8, Freeman MP9, Maes M10, Matsuoka YJ11, Belmaker RH12, Jacka F13, Pariante C14, Berk M15, Marx W13, Su KP16,17.
Author information
Abstract
Major depressive disorder (MDD) is a complex mental illness with unmet therapeutic needs. The antidepressant effects of ?-3 polyunsaturated fatty acids (n-3 PUFAs) have been widely reported. The subcommittee of the International Society for Nutritional Psychiatry Research organized an expert panel and conducted a literature review and a Delphi process to develop a consensus-based practice guideline for clinical use of n-3 PUFAs in MDD. The guideline focuses on 5 thematic areas: general concepts, acute treatment strategy, depression recurrence monitoring and prevention, use in special populations, and potential safety issues. The key practice guidelines contend that: (1) clinicians and other practitioners are advised to conduct a clinical interview to validate clinical diagnoses, physical conditions, and measurement-based psychopathological assessments in the therapeutic settings when recommending n-3 PUFAs in depression treatment; (2) with respect to formulation and dosage, both pure eicosapentaenoic acid (EPA) or an EPA/docosahexaenoic acid (DHA) combination of a ratio higher than 2 (EPA/DHA >2) are considered effective, and the recommended dosages should be 1-2 g of net EPA daily, from either pure EPA or an EPA/DHA (>2:1) formula; (3) the quality of n-3 PUFAs may affect therapeutic activity; and (4) potential adverse effects, such as gastrointestinal and dermatological conditions, should be monitored, as well as obtaining comprehensive metabolic panels. The expert consensus panel has agreed on using n-3 PUFAs in MDD treatment for pregnant women, children, and the elderly, and prevention in high-risk populations. Personalizing the clinical application of n-3 PUFAs in subgroups of MDD with a low Omega-3 Index or high levels of inflammatory markers might be regarded as areas that deserve future research.
© 2019 S. Karger AG, Basel.
KEYWORDS:
Docosahexaenoic acid; Eicosapentaenoic acid; Guideline; Major depressive disorder; Omega-3 polyunsaturated fatty acids
PMID: 31480057 DOI: 10.1159/000502652
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Cont... Among 1st publication in AHA Journal that elucidates effect of EPA Metabolites into thin-cap plaque than thick-cap plaque at 3 weeks after the administration.
Bodes well for Evaporate
https://www.ahajournals.org/doi/10.1161/ATVBAHA.119.313093
Highlights
Eicosapentaenoic acid is preferentially incorporated into the thin-cap plaque than thick-cap plaque at 3 weeks after the administration.
Eicosapentaenoic acid is incorporated from the lumen and mainly exists in the plaque as cholesteryl esters.
Successful tissue imaging of hydroxy-eicosapentaenoic acids shows their colocalization with administered eicosapentaenoic acid and the M2 macrophages.
AHA Journal: EPA
Tweet liked by Dr Bhatt
n-3 PUFAs, especially EPA have beneficial effects on atherosclerosis.
— ATVB: An AHA Journal (@atvbahajournals) August 31, 2019
Administered EPA trends to be incorporated from the vascular lumen side, and preferentially taken into the thin-cap plaque.https://t.co/OfiWhWikeH pic.twitter.com/ZL3CZJq5nw
Thank you Mellow - excellent analysis
V-Day
Don’t sweat small stuff, the recommendation to use icosapent ethyl is a license to drive billions out of Euro and beyond
on 9/2 the trio of EPA for CVD thought leaders gives ESC the scoop on
R-I results, urgent need (Dr Bhatt) MOA and issues with supplements (Dr Preston Mason) and Weintraub on Clinical use
The PR coming next week will be an avalanche burying shorts
New Euro guidelines for using Vascepa is a perfect setup for 9/2 talk in Paris by Bhatt Weintraub and Mason on R-I findings.
https://www.escardio.org/The-ESC/Press-Office/Press-releases/european-guidelines-on-lipid-control-advocate-lower-is-better-for-cholesterol-levels
CONCLUSIONS: EPA may be a promising therapeutic approach to improve outcome in septic patients.
ncbi.nlm.nih.gov/pubmed/31443678
?Dr Bhatt?
?SUMMARY
“Icosapent ethyl was rigorously shown to decrease residual risk for cardiovascular events, though the benefits seen were likely because of mechanisms beyond mere triglyceride lowering. Clinical application of icosapent ethyl in this cohort of patients with residual risk is URGENTLY NEEDED. “
?https://www.ncbi.nlm.nih.gov/pubmed/31464773?
JAMA Death from heart disease rising
https://www.cnn.com/2019/08/27/health/heart-disease-stroke-diabetes-death-rates-study/index.html
Polypill cuts CVD risk (video)
Heart Failure
https://www.mdpi.com/1422-0067/20/16/4025
How many billion people is this that can benefit from Vascepa ?
https://d2tod6vzwskp8g.cloudfront.net/ESC2019/Scientific%20Programme/197160/Abstract/P651.pdf?Expires=1566591069&Signature=KGSySqkoVtS1~006rIAW2judiofQq6h9oqnhI4OT8FlK4jSnpy04QFo7qs0vNuzQp2WHZpN10aq9n~i0beBktfcSIq82GsFQ-CuhSDn3BEd7~0brL9pfs5lukX7orU~Oz4jZ6nWGbs4ls748HhVTqAIMrl~t6QmggsAseylK~gx2gP92zJ3os-KlCMWvouqTmTmCDlCrS-OY0SGD2LOkY8-zuz3ZatsX2NLvqLfUBmimCGDEU12P8eVge~AzsDSaBntRQQuaQMeG6d-fBjQ~BA1CgBGmbmU1EnCxsyBaBw9nIbYxhkgozo-n~dtcbWR7zd~zjm1E-YqRU3em6~Atcg__&Key-Pair-Id=APKAIWNNOMINYCK536DA
View into FDA internal rancor over approval decisions
https://undark.org/article/fda-eteplirsen-janet-woodcock/
Have some appreciation for tough spot endo unit is in. They’re struggling with the label as it’s not their domain
Simple as that
Raf, put yourself on BOD, and you are asked what label to go for.
How many billions do you go for, how many billions do you walk from?
How much time do you need to answer?
Odd, the variance in labels was already thoroughly discussed here and handicapped .
If BOD of Amarin didn’t seek broadest label possible they wouldn’t have done their job for us.
Think... what is 1st priority of BOD?
Nah, you’re thinking too much. Far simpler. Endo unit finds themselves in uncharted area. Amarin put them in position to having to decide on changing the way CVD is treated. That’s not a decision they feel is in their court - and hence hand wringing and reacting to Amarin’s (likely) broad unconditional label requested with seeking consensus, air cover. Amarin has put FDA Endo unit in tough place.
FDA needs to put the big boy pants on and do their job. But easier said than done. They will be dialing up for advice, internal meetings and collaboration with CVD unit. Adcom is noise, but gives them the air cover so they’re not viewed as renegades, roaming off the reservation. Had Amarin bent over and submitted a narrower label, the FDA would have been relieved
BB, you’re usually out on the fringe... but can anyone envision FDA bucking AHA on treating HTG with V? Between, consensus with ADA, AHA, and CVD thought leaders - FDA Endocrinology is backed into corner.
Want to know what’s happening behind scenes? Think, can you imagine the board discussion on which label to apply for?
Here’s a fictitious board discussion
“Do we argue for broad label, prevention of CVD - no other conditions and piss off FDA? Our fiduciary responsibilities are to create maximum shareholder value. Yes, there may be repercussions and possibly delays and probably an Adcom, but this is a once in a lifetime opportunity. I say we go for broadest label - damn the torpedoes !”
JT-
“ I agree”
Thanks Sam, strong numbers
They will not market DTC on any indication not approved by FDA- it’s as simple as that and folly to think otherwise. They are already blasting Docs with Reps and KOLs.
Now on related topic, the advisory and endorsement of AHA of the Anchor indication this week is telling. On one hand, it seems to have been released in a vacuum- without knowledge of R-I results. But perhaps not. A 30M patient pop indication is nothing to sneeze at and won’t be lost on FDA. Would FDA negotiate an expansion for Anchor label near term and work towards CVD prevention without crippling Amarin allowing FDA to CRL to ascertain MO issue? I don’t have a crystal ball, but having that label would allow DTC marketing of Anchor which FDA agrees is all about CVD and would allow Amarin to mention R-I results DTC while discussing reducing HTG. It was the FDA that admitted the only reason to lower HTG was for CVD prevention. Next few months will be interesting
AHA grants Anchor indication
https://www.medpagetoday.com/cardiology/dyslipidemia/81701
tweeted by Dr Bhatt:
Howard Weintraub on REDUCE-IT Data: 'Very Exciting Time'
https://www.medpagetoday.com/clinical-connection/cardio-endo/79480
MO side effects
Common side effects of mineral_oil include:
Lipid pneumonitis if ingested in reclined body position
Fecal incontinence
Intestinal malabsorption
Impaired absorption of fat-soluble vitamins
Rectal discharge of mineral oil
Anal itching and irritation
Abdominal cramps
Nausea
Vomiting
Lipid pneumonitis with aspiration
Serious side effects of mineral oil are rare and include:
Difficulty breathing
Persistent cough
This is not a complete list of side effects and other serious side effects may occur.
What did DMC find with 4gm daily?
Mineral oil as laxative is 15 to 45 ml
Or roughly 13-17gm if my math is right
https://www.rxlist.com/consumer_mineral_oil_kondremul_plain/drugs-condition.htm#
Statin Absorption
Atorvastatin is readily absorbed after the oral administration. Multiple daily dosages in the form of 2.5–80 mg capsules produce a maximum steady state concentration (Cmax) of 1.95–252 µg/ml within 1–2 h. The AUC increases in proportion to the dose of atorvastatin, but the increase in Cmax is greater than for the proportional dose. The low systemic availability is attributed to the presystemic clearance in gastrointestinal mucosa and/or hepatic first pass metabolism. Food significantly decreases the rate, as well as the extent of absorption; Cmax and AUC decrease by 48% and 13%, respectively.
https://www.sciencedirect.com/topics/neuroscience/atorvastatin
Kiwi, is there any possibility the FDA considers the 15% primary EP to be in question? That’s the line-in-sand that needs to be crossed for any label expansion to be nixed.
VuBru, Dr Bhatt answered your question today
https://www.mdmag.com/medical-news/bhatt-subgroup-analyses-reduce-it-trial
Bhatt: The primary endpoint of the REDUCE-IT trial was so-called 5-point MACE—or major adverse cardiovascular events—meaning cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or revascularization. This was significantly reduced in the overall trial—about a 25% relative risk reduction—that was highly statistically significant. As well, the key secondary endpoint of cardiovascular death, MI, stroke—so-called 'hard MACE,' was also significantly reduced by about 26%.
We've done additional analyses of the data looking not just a time to first event—the conventional way of doing such analyses, but instead also looking at total events—that is, the sum of initial events and recurrent events—and have found a 30% reduction in total events, which from a patient's perspective, of course that's how they look at things. Patients care about having second events.
That is, they'd rather not have a stroke after MI or a cardiovascular death after an episode of unstable angina. So, from a patient-centered perspective, perhaps the total events is really the more appropriate way of looking at data—though the conventional historic way is time to first event, but really any way you slice the data significant reductions, both in relative and absolute terms, in important ischemic events.
We've also examined a number of different subgroups. Most recently, patients were examined by their baseline tertile of triglyceride levels, and what we found—not that the trial was designed or powered for subgroup analyses such trials never are—but we did find significant reductions in ischemic events in all 3 tertiles, including the lowest tertile of baseline triglycerides. And that included patients with triglycerides as low as a 100, even though the inclusion criteria as stated was really 150, but we allowed variation and triglycerides.
And indeed, there was even greater variation when we looked at an average of a couple of measurements—as is known to be the case of triglyceride. So, bottom line is we got patients with triglycerides as low as a 100, but even those in that range of 100-150 or so seemed to derive substantial benefit from icosapent ethyl versus placebo arguing—at least indirectly—that some of the benefit might be beyond just triglyceride reduction.
Negotiations recorded
AMRN: Data shows any TG level benefits from icosapent ethyl at risk of CVD
FDA: that's 60M Americans!
AMRN: Yup
FDA: So you're asking us to approve a label for anyone at risk of CVD?
AMRN: Yes, 60M Americans will benefit
FDA: But you're NOT an LDL-C lowering therapy. You're asking us to tell 60M Americans to take icosapent ethyl and Statin therapy?
AMRN: Yes
FDA: If you want that label for 50% of adults in US, we'll have to convene Adcom. Still want that label?
AMRN: Yup, the data is clear and definitive
FDA: What about mal-absorption from Mineral Oil? If it's true perhaps the reduction is overstated.
AMRN: We believe RRR is understated. Separation of arms is clearly continuing beyond 5 YEARS. And MO issue is nonsense. What if Crestor group had the same event rate as the group on fat-soluble statins? How can that be if MO was supposedly increasing event rate in Fat-Soluble statin therapy but not in water-soluble Satins?
FDA: This will change everything, practice-changing. AHA has to be on board. We cant approve such a broad label on our own. We'll need an Adcom. Besides, we are Endocrinologic and Metabolic Drug team, not CVD.
AMRN: Whatever dude... Don't forget we have 1st Amendment rights to talk about R-I anyways. And with ICER, AHA and 85% of cardiologists are on board this should be no brainer.
FDA: are you saying we are no brainers?
AMRN: How many CVD deaths occurred since 2013?
FDA: Are you accusing us of murder now?
AMRN: Data speaks for itself.
FDA: OK OK, Adcom is coming your way MoFo! What is Nissen's telephone number? OH yeah, you have it via FOIA?
AMRN: See you soon
FDA: bye
AMRN: bye