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Well stated !
Question: Is the voting tally determined by the number of shareholders voting FOR vs against or total number of shares voting FOR vs against?
Marjac, I am fairly confident that Hikma et al are scrutinizing in detail all your statements available on a public forum.
I would suggest you keep any Ace’s up your sleeve well concealed until “showtime “ ….
I write “ DAW1” on my prescriptions and that avoids any pharmacy substituting
Ralphey,
Several pharmacists are not familiar with Reduce-It indications.
I am writing on my Vascepa prescriptions “DAW1”
This prevents the pharmacists from substituting.
A great deal of these studies are in vitro.
For someone who has engaged in in vitro, animal in vivo and clinical studies it is very clear that one may observe a set of in vitro properties of an agent which supports a potential positive benefit. This hypothesis when tested in a double blind placebo controlled trial ( the gold standard of scientific evidence in clinical medicine) may show very divergent results.
I myself have observed the same dichotomy in my own research over the past few decades.
A very humbling reminder by Mother Nature indeed.
Numerous examples of this have emerged over the past few decades. The HERS study is just one example of this ! For years it was postulated that one reason why women tend have a lower risk of heart disease than men was due to the “cardiovascular protective “ effect of estrogen in pre-menopausal women and once menopause occurs, this protective effect is lost. Many physicians and gynecologists for years promoted hormone replacement therapy in women as being cardio-prospective.
When the HERS study was published to test this hypothesis, the results were to the contrary.
In my opinion it is futile to throw countless in vitro or poorly designed clinical trials in the face of CardioMD when he is simply stating the rigor of scientific evidence that we as clinicians use to practice evidence based medicine.
Yes, I have reviewed articles published by recognized “experts” holding MD. PhD degrees from “respected” institutions ( including MIT ) who posit subgroup analyses and poorly designed clinical trials as hypothesis testing rather than hypothesis generating.
Over the years it has become less surprising to me how few MD PhDs are familiar with the application of statistics in clinical medicine.
AVII, on this board, in my opinion stands out uniquely in his in-depth knowledge on statistics.
In fact, it was AVII, ( thank you AVII) who introduced me to the work of the outstanding biostatistician, Fleming, who certainly is a great educator for those who would like to study this subject matter in greater detail rather than flinging countless non conclusive studies onto this board, hoping that 1000s of inconclusive results would leap into a category of conclusive evidence.
JL : The Vascepa label was revised 12/19.
The new label incorporates the R-It data AND the sentence “ The effects of Vascepa on cardiovascular morbidity and mortality in patients with severe hypertriglyceridemia has not been determined “ has now been DELETED.
The Marine indication otherwise still stands.
Other caveats in the new CV indication:
No upper threshold for TG : >= 150mg/dL,
Maximally tolerated Statin ( which could imply zero Statin) ;
No age limitations:
As Type 2 Diabetes is not specified, Diabetes in the label implies both Type 1 and 2;
HDG ! Welcome back . How do you interpret “holistic” mentioned several times by JT on the conference call?
Outstanding DD Hamoa and HD
Thx HD and Hamoa !!
Well stated. Professor Leung Gabriel, an international authority on Coronavirus is a refreshing voice of scientific lucidity to listen to.
He was featured on Australia 60 minutes during the first week of March.
He displays a clear scientific message untainted by any political bias with hands on grasp of the subject supported by stellar scientific credentials.
This Australia 60 minutes interview and others featuring Leung Gabriel are readily available on YouTube and worth listening to for those of us engaged in the rapidly evolving challenges in the medical profession and others who have a scientific curiosity with zero interest in the pathetic game of political ping pong....
Oh my HDG! I believe you are correct!!
It does appear that the Board is engaging in discussion more and more removed from reality!
On October 25, 2016, Amarin announced the introduction of a smaller 0.5 g capsule size. This was a wonderful welcome to health care professionals as there have been some patients expressing concerns in swallowing the 1g sized capsule.
Since then I routinely show my eligible patients both sizes and allow them to choose.
With the introduction of 0.5 g size for those having challenges in swallowing larger sized pills, taking 4 capsules twice daily with meals has not been a concern.
Many of my patients have had family members undergo chemotherapy with daunting side effects to provide them the chance to spend a little more precious time with their loved ones.
When they hear the stroke, heart attack plus death benefits of Vascepa they are more than willing to take 4 or 8 capsules daily of a medication with relatively minuscule side effects compared to the oncology agents and such astounding benefits! I am pleasantly surprised how the spouses are so resolute in ensuring compliance with V. They certainly care about their loved ones and when they hear prevention or heart attack, stroke and death, the resolve is immediate!
We are referring to patients with increased CV risk who may have been recently discharged from hospital for a stent or vascular procedure or Type 2 Diabetics with increased CV Risk who know of family members or friends who have suffered CV events.
V is a medication which saves lives and there has been no medication since Statins that have achieved such robust CV benefits!
The fact that V is derived from and carefully processed from “nature” adds another positive to patients perception and acceptance.
The major challenge has been to educate patients on the differences between V and DS.
The elegant research by Preston Mason makes the task easier and so does the ADA critical update to SOC in March, 2019.
The ADA SOC clearly articulates this difference “it should be noted that data are lacking with other omega-3 fatty acids, and results of the REDUCE-IT trial should not be extrapolated to other products.”
VBru - Kiwi may have a point.
While R-It included patients with TG 135-499, the tertile analysis published in JACC this year indicated that patients with TG <100 in the lower fertile and above 500 in the upper textile were also captured in R-It due to the intra-patient variability of TG levels. As you correctly pointed out that the number of subjects were smaller in these two extremes.
However, if the FDA is going to consider TG>135, then 500+ would be included in such an analysis. One can argue that if the upper tertile of TG is being included in consideration by the FDA, then the lowest tertile may similarly warrant inclusion for consideration.
It may all come down to the number of subjects in these two extremes.
Just as LDL-C is no longer a required threshold to initiate Statin therapy in Type 2 Diabetics, similarly TG may disappear as a required threshold in initiating V in at risk patients.
VuBru and AVII ( if available) It certainly was a pleasant surprise to me that the ADA, included both the Secondary Prevention ( SP ) and Primary Prevention (PP) population in their urgent SOC.
If one looks at the R-It data the SP benefit was clear however the PP benefit CI just crossed unity. While R-It was not specifically designed to test PP per se, one can argue that a separate PP study would be required to validate the benefit in the PP population.
I am not sure precisely what reasons ( although I am glad they did ) led ADA to include both populations, but if one looks at the robustness of the data with 7 zeros after the decimal point in the p value for the 5 point MACE, and the consistency in benefits with numerous secondary endpoints including the most evasive CVE of CV mortality, one can perhaps understand how the ADA may have concluded to include the precise dermograhics of R-It in the ADA SOC, designating it the highest level of scientific standard ( level A ).
It is possible that the FDA is trying to wrap its head around whether the indication should only include the SP or both SP and PP and to address the importance of this question an ADCOM may have been the most reasonable pathway to resolve this important question.
Vascepa Extraordinaire! The very first to successfully take on the big 3 : Death, Heart Attack and Stroke beyond Statins!
Good Evening AVII!!
Many many thanks for sharing the Fleming video and taking the time and energy in addressing this question of subgroup analysis!
I found one illustration by Fleming ( at 44 minutes into his talk ) relating to KOLs very enlightening! How easily clinicians can come up with “plausible explanations “ to fit post hoc subgroup analysis which in essence are exploratory and equate such conclusions as “proof” even when the primary endpoint in a trial had failed to show any significance!
The clinical trial illustration at 44 minutes is certainly a classic for the ages!
Wow, wow, wow AVII !
Thanks for sharing and yes fully answered my question which had nothing directly to with Reduce-It but rather with the prior failed Fibrate and Niacin trials where some of the sub-groups analyses were hypothesis generating.
I have had a colleague argue with me that the subgroup analysis in some of these failed trials provided “proof “ that some sub-populations benefited when there was a “significant p value” in the post hoc subgroup analysis!
This has been a recurring and very concerning issue in Clinical Medicine and Fleming certainly provides a great insight into this question!
Agree, great educator !
Thanks again AVII!
Excellent and very wisely weighed summary of events JL !
Your deep insights and years of experience are elegantly reflected in this analysis!
AVII : Question. Do you have a good reference/source which clearly states that subgroup analysis of a trial is essentially hypothesis generating if such endpoints were not pre-specified in the primary objectives of a trial. Always enjoy your input !
AVII. ! Elegant interpretation indeed !!
Your argument clearly illustrates the importance of not withholding treatment to a subgroup based on a trial such as Reduce-It . The importance on non significant interactive p value clearly applies as you beautifully carefully illustrated.
I must confess when I first read the NEJM paper I was trying to unravel whether the non significant interactive p value which indicates that both the Secondary population and PP had similar benefit contrasted with the fact that the CI for the PP of 0.70-1.10 may potentially negate such a significant benefit in the PP. - I was trying to determine which of the two had greater statistical relevance, interactive p values or CI .
The subgroup analysis with the application interactive p value was pre-specified and R-It was not designed to test the PP population per se .
Hence the interactive p value ( in my mind ) was the key take away message that there was no statistical difference in benefit in the Secondary and PP.
You have beautifully dissected and interpreted this AVII !
The good news is that the ADA with it’s esteemed panel, AVIi, appear to have embraced this as well !
Congratulations buddy !!!
Absolutely great news for the at risk patient population!!
Hopefully this will make the challenge for Amarin to place V on preferred status much easier with the various Insurance Companies and also provide a basis for the FDA to endorse ADA ! I was wondering whether FDA may only give the nod for Secondary Prevention but it appears that the ADA made it easier to embrace the entire R-It population. For those still reluctant Insurance Cos, a follow-up of a cost effective analysis of Total events should erase the doubts in the minds of the few remaining skeptics!!
Now all we need is Elaborate to display one more piece in the amazing MOA of V and BRAVE to open a new chapter for V!
March certainly has provided a window for Interesting times ahead !
Thanks for sharing! HDG and others, question!
Branded OTC beyond 2029 into perpetuity worth $500 million per year ( if I heard correctly) has not been appreciated!
Apparently the likes of PFE have already been doing this !
This is something new to me !
Any thoughts from the business savvy minds on the Board?
AVII : just reflecting on Total events.
There was a landmark publication by Steven Haffner referred to as the “East West Study” published in the NEJM in 1998 and widely presented at Diabetes conferences for well over a decade after that date. There was a classic slide derived from this study which really has been imprinted in our minds and is vividly remembered even up to this very day !!!
The investigators posed a simple question; What was the risk of an MI in a non-diabetic ( NDM ) over a 7 year time period who had not had a prior MI compared with a non-diabetic who had experienced a prior MI and juxtaposed this same question for diabetics. ( North FYI, these were Type 2 Diabetics and not Type 1 Diabetics ).
The results were simply amazing!
Risk of MI in NDM without prior MI : 3.5%.
Risk of MI in NDM with prior MI : 18.8%.
Risk of MI in DM without prior MI : 20.2%.
Risk of MI in DM with prior MI ; 45%,
The conclusion; Type 2 Diabetics without a history of prior MI have the same risk of developing an MI as a non Diabetic who has suffered a prior MI!
This was a paradigm shift in the perception of Type 2DM and risk for long term complications! This landmark trial set the stage for Type 2 DM as being a CVD risk equivalent. All the guidelines including ADA and AACE changed where the philosophy of treating Type 2DM from a glucocentric approach where only the micro-vascular complications were considered to that of embracing the more enormous CV burden that Type 2 Diabetics face. Many KOLs at Diabetes conferences after the East West publication referred to Type 2 Diabetes as “Cardio-Diabetes” to encompass the important CV burden of Type 2 DM. Algorithms for Type 2 DM since then have included not only optimizing A1C but also decreasing CV burden with anti- platelet agents. Statins, Blood Pressure treatment. More recent guidelines have also included Type 2 DM glycemic agents which have shown CVE reduction such as SGLT 2 Inhibitors and GLP-1 agonists.
With this background if one considers the Demographics of the R-It population:
70% Secondary Prevention;
58% Type 2 Diabetics.
Total events to be considered include MI,
Stroke, hospitalization for unstable Angina plus coronary re-vascularization.
These events are way more than just the single MI endpoint in the landmark East West Study.
The importance of the presentation of Total events on 3/18 cannot be understated! ( AND Bhatt clearly knows that ! ) !!
That a dawn of a new paradigm, well beyond that of the landmark East West publication, is on the horizon is without question a reality which is unfolding in front of our eyes !
The total event data will not only allow clinicians to appreciate the magnitude of clinical benefit, but set the stage for Guidelines to follow ( after the seal of FDA approval) and Insurance Cos to willingly allocate V in a preferred status ( cost benefit analysis really being a no brainer even to the most mentally challenged! ).
AVII , like you, I am really really looking forward to the 3/18 presentation !!
Thanks Babr!
Perhaps Bhatt presentation of total events will hopefully will be a wake up call for those still in the dark.
Thanks AVII ! And thanks BB for your earlier reply.
BB, I know that you are very familiar with the data, but in my opinion, the magnitude of effect of V on total events vs the more modest effect of PCSK9s, in my opinion will be the lingering message in the minds of the audience at ACC on March 18, many of whom are still be trying to get to grips with this new information. The unfamiliarity with the data among many of the MDs are meet is quite striking.
I just met a Cardiologist, who readily prescribes PCSK9s, the other day who asked me whether I believed the R-It data and expressed no knowledge of Jelis, differences between DHA and EPA, nor the NNT of 21 in R-It.
I believe that the audience seeing both Odyssey and R-It total events on the same day will be very sobering for many and rightly place V in a category all by itself.
BB, AVII and others - question?
Do you know whether the total events presentation at ACC for Odyssey and R-It are going to back to back ?
At AHA, Vital and R-It were presented in succession to the Cardiol audience.
The message at AHA clearly set EPA as distinct from DHA.
If the PSK9 and V data are similarly presented at ACC, the audience will get a clearer perspective how V stacks up against the most effective ( and expensive ) add on to a Statin !
If the total events for V are mind blowing, Cardiologists will see the immediate impact of the significance of these findings for patients throughout the world.
Thanks for sharing North ! Minor typo :
You meant every 38 SECONDS!
All the best !
On the topic of HDL-C.
The science in this area has been complex and still evolving to say the least.
The earlier 'relationship" between HDL-C and CV risk appeared to have orginated from Framingham.
Researchers at the time acknowledged that HDL-C and TG were invariably inversely related and "incorrectly" attributed the increase in CV risk to low HDL-C rather than the elevated TG .
TG were frequently dismissed by KOLs as a CV risk factor and HDL-C was hailed as important second to LDL-C.
I recall delivering a lecture on Lipids to a group of Physicians in Denver several years ago and the typical question on HDL-C arose during Q&A session.. At that time I had just read about the exciting data on Apo-A1 Milano, where in a small town in Italy a family tree of very low HDL-C often in the teens had the unexpected observation of increased longevity and DECREASE in CV risk. I shared this data with the audience and how Cedars Sinai was exploring this further by injecting this Apo-A1 variant to subjects with atherosclerotic plaques and demonstrating significant plaque regression. Without even conducting a CV outcomes trial, the small Biotech Esperion which had developed this Apo-A1 variant in the laboratory, was purchased by Pfizer.
This was my first exposure to the science demonstrating that it was not the quantity but rather the quality ( functionality ) of HDL-c that was the key in the HDL-C space.
However, many lipidologists at the time were still focused on raising the amount of HDL-C.
CETP inhibitors were the next big wave with regard to HDL-C.
BPs such as Merck, PFE, Lilly, Roche, devoted large $ in R&D towards CETP inhibitor research realizing that these agents could raise HDL-C by >100%. The "potential" for such elevation in HDL-C was considered by the experts to be huge at the time.
Then the CETP CV Outcome trials (CVOT) followed one after another with each one failing in turn.
These included PFE, Lilly, Roche and Merck.
Merck was perhaps the only BP publishing favorable CVE with their CETP inhibitor but soon thereafter announced that the Co was not going to move forward with NDA to the FDA and that marked the end of the CETP chapter.
Articles in the media that followed essentially summarized the great expectations of CETP inhibitors ending with greater disappointments. I recall titles such as "Blockbuster that wasn't", "Trials and tribulations of CETPs" etc etc.
It was very clear that BP had poured huge $ on the HDL-C hypothesis.
Subsequent trials of Fibrates and Niacin as add ons to Statins failed repeatedly in their CVOTs.
The FDA reviewed the risks vs benefits of Fibrates or Niacin as add on to Statins and redacted the indication of Fibrates or Niacin as add on to Statins in reducing CVE.
More recently elegant genetic research by Dr Amit Khera, a rising star in preventative Cardiology out of Harvard, demonstrated that LDL-C and TG independently correlated almost equally with CV risk while HDL-C had zero correlation.
Dr Khera explained that population studies on HDL-C and CV risk were confounded by the inverse relationship of HDL-C and TG, and scientists 'selected" HDL-C over TG. The genetic studies were able to study this lipid particles independently.
This was perhaps the "nail in the coffin " for the focus on HDL-C quantitatively.
More recent research in this area has been focusing on functionality of HDL-C, and this is still a very complex evolving area.
While it is a fact that V is associated with a decrease in HDL-C, the clinical relevance of this, if any, is still unknown.
Preston Mason has also demonstrated interesting effects of EPA on HDL functionality.
We are all aware of the amazing RRR in R-IT and the Total events to be reported at ACC, as mentioned by AVII, may be even more breathtaking.
The history of add on to Statins has been a very challenging and difficult road for scientists and BP.
The modest 6% RRR with Ezetimibe add on with no CV mortality benefit and the 15% RRR with PCSK9s with no CV benefit has left BP thirsting for some glimmer of hope to address the disease which contributes to the highest mortality risk in the USA - CVD.
With this history over the past three decades, with billions of $ spent by BP searching for something beyond Statins, Amarin comes a small Biotech comes up with such amazing results with R-It.
To state that BP, like huge whales, after spending billions on R&D on coming short, must be salivating at the R-It results, may be an understatement of the decade or of the century.
JL. BB, VBru, AVII have all probably touched on the significance of these findings.
Clinicians on this board may appreciate what this means for the health and lives of the at risk patients.
The magnitude of the implications of this science has still not sunk in.
Perhaps, ACC March 18, may be another wake up call for some.
This is unchartered seas, and for those of us on this journey, 'buckle up" may be the thing to do!
Thanks for sharing AVII!
Bhatti to present under “Scientific Breakthroughs Practice Changing “ Session on Monday March 18 !
I am certainly looking forward to this very clinically relevant presentation - just a day after St Patrick’s Day !
It looks more and more like V as an add on to Statins to reduce residual CV Risk is heading towards the new SOC !
The sNDA is supposed to be submitted before the end of first quarter!
March may be a very interesting month for Amarin!
Thanks AVIi.
I guess the devil is always in the details!
It just appears as crossing over into “misleading and not truthful “
AVII : Do you know how authors sneaked this into the Abstract of the article?
Was this an oversight by the Editor of JACC?
The way the Abstract reads, Total mortality was also “decreased” !
The audio summary also stated this total mortality “benefit”
I have a feeling that the Reps are running with this Hypothesis generating mortality data and stating it as a done deal, particularly with the ambiguous wording of the Abstract.
Thanks AVII for the helpful input on Odyssey and the audio!
Question:
In the Primary Report of Odyssey, based on pre-specified sequential ( hierarchical) analyses, CV mortality showed no independent benefit and Total Mortality below revealed a “nominal” p value = 0.026 which essentially implied hypothesis generating.
In the more recent Total events report of Odyssey, the authors mention the original publication of total mortality and indicate that this “observation “ of decrease in total mortality was again “supported”.
Is this a clever play of words or statistical gymnastics?
The Abstract of this paper includes decrease in total mortality and the audio you kindly shared with us also mentions the same statement.
Two of my cardiologist friends last week shared with me that the Pharma Reps are telling them that that Odyssey did show a mortality benefit!
Is this a valid scientific take from a pre- specified analysis which I interpret as exploratory or hypothesis generating?
Two hypothesis generating statements do not add up to a hypothesis testing conclusion! Do they ???
Would appreciate your input AVII !
Good job CardioMD !
After March 18, when Bhatt presents at the
“ Breaking News Practice Changing “ session on R-It at ACC, the impact of the significance of the data translating to practice changing clinical relevance will have to sink into the minds even of those who “hate to admit” ( due to conflict of interest) that an add on Rx to Statins surpasses even what the “unbeatable” amazing Statins by themselves have achieved thus far :
Statins. V ( add on )
MACE RRR 20-25%. 25-26%
Absolute RR. 1-2 %. 4.8%
NNT. 40-60 21
Simply amazing! No other conclusion can be drawn from the overwhelming evidence!!!
Total reduction in Ischemic Events from R-It to be presented at ACC on March 18, may even surpass 30% !!! With yet another string of zeros in the p value !!
Thanks BB ! There is only one HULK on this Board !
Thanks for all you do !
Welcome Chemis ! We are journeying together friend !
Thanks AVII.
It is really wonderful to see your amazing skill and knowledge at work and more than that you make the dedicated time to find the supporting evidence to support your statements - with all that you have the knack to hone in directly to the question at hand !
I always appreciate your valuable input to the Board, and I’m sure I echo the sentiments of many in stating that !
Sorry typo in original message:
NorVit Trial revealed despite ~28% decrease in Homocysteine levels with mixture of B Vitamins, CVE increased.
Thanks Kiwi!
As you astutely noticed, although I did not direct the post to CardioMD, I hope he reads it !
This is an amazing journey and we haven’t seen the final chapter yet!
Thanks Babr!
My apologies for not mentioning everyone on this Board including you !
Appreciate you Babr!
On the threshold!
We are on the threshold of a major paradigm shift in the treatment and prevention of CVD and EPA is taking center stage.
This is something many of us will probably never see again in our lifetime and those who have boarded the train years ago on this Board will hopefully be able to share this amazing ride with loved ones and friends for years to come.
Thanks Dancing for sharing about the sad passing of a key researcher in the EPA space, sadly before R-It Trial reaching completion and the dramatic presentation st AHA.
That there are members on this Board with diverse backgrounds goes without stating. However, among the many there are some very unique members who have over time almost become like members of a large family. Just to name a few :
BB, JL, Vbru, North, FFS, Sam, SK, AVII, Kiwi, STS, HDG, CardioMD, TTE, Chas, Marzan, AnonFish, KevGee, Dancing in the dark, ZIP, RetinaMD, Bfost, etc etc etc.( apologies for not listing others ).
Like in any big family one has to sit back and see the big picture and not be distracted by nuances of idiosyncrasies of personality.
That JL can let off steam is probably an understatement! That JL is bright and knows a great deal about O3s and EPA and inflammation goes without saying! In this context JL has brought a great deal of value to the Board!
That JL tends to connect dots in his thesis is also evident and can be irritating to many and such irritation is justified as one needs evidence to support such hypotheses - eg SI, IR, FAS etc.
However, this is no way erases all the immense value that JL has and continues to bring to the Board.
We have all lived and learnt over the decades about proposed hypotheses and their demise with subsequent outcomes trials.
Several decades ago it was hypothesized that the reason why postmenopausal women have an increase in CV events compared to women prior to menopause was due to the “cv protective effect of estrogen” in premenopausal women. For years HRT was promoted as providing CV benefit in women following menopause in addition to other benefits. Then the HERS and WHI Trials were published and researchers had to humbly acknowledge that HRT INCREASED CVE and Pulmonary embolism and Breast Cancer in postmenopausal women. The “CV benefit “ hypothesis of HRT was put to rest.
Similarly, years ago , Cardiologists had hypothesized that Homocysteine was an important marker of CV risk ( based on genetic studies). Armed with this hypothesis, cardiologists and PCPs started to measure Homocysteine levels in at risk subjects and found that Vitamin B12, Vitamin B6, and Folic Acid would decrease these “elevated “ Homocysteine levels by 20-30%. Prescription grade mixtures of these Vitamins became readily available ( Folbee, Metanx, etc ) and often were added to other meds for cardiac patients almost as routinely as adding Aspirin. Then the Outcomes trials surfaced where cardiac patients received these mixtures and despite a 28% decrease ( which was expected) CVE tended to increase! NorVit ( Norwegian Vitamin Trial ) and HOPE 2. In fact the title of the presentation at the European Cardiology meeting was : “ Is Homocysteine dead “. Another hypothesis put to rest.
I recall attending an Endocrine Conference years ago in New Orleans where we enjoyed a presentation on how Cyclosporine in vitro inhibited a family of Interleukins. One of the hypothesis at the time was that estrogen deficiency mediated it’s effects on bone turnover and resultant postmenopausal osteoporosis was via various Interleukins . We promptly returned to Philadelphia and administered Cyclosporine to surgically induced menopause ( oophorectomy ) in rats with the hypothesis that the bone turnover would be favorably influenced histologically. I can still remember receiving a call late on a Saturday night from the Histomorphometrist at UPenn asking me what the hell we were giving to rats as the bone volume had so dramatically decreased. We called the manufacturer of Cyclosporine and advised them to send us a new batch and repeated the study with a dose response design . Not only was our hypothesis turned upside down but this opened a new chapter and Chief of Endocrinology whom I worked with became an authority on Immuno- suppressive induced bone disease.
Mother Nature is far too smart and hypotheses are just that. As one tests these hypotheses over the years one naturally develops a humility to the wonders of Mother Nature.
On the subject of humility, it is important imo to keep an eye on the big picture.
CardioMD is a relatively new member to the Board and I do find his contributions of value. He comes across with great integrity and sincerity with a spontaneous expression of care and compassion for his patients and a strong focus on the science and respect for KOLs in the CV space. At the same time he speaks his mind and doesn’t hold back - I personally respect him greatly for that. All these great positive traits of CardioMD were not in the least diminished when I recall him expressing that Endocrinologists deal with “hormones “ and not CV research or lipids ( I am quoting on recall and although the verbiage here may not be precise that was the theme of that statement ) . Well, I have as an Endocrinologists worked with Evan Stein MD, Ph D. in Cincinnati in his Lipid Research Laboratory and Evan is an earlier pioneer in CV research ( LRC-CPPT etc ). I subsequently returned to Philadelphia and directed the Cholesterol Treatment center and published in the Diabetic, Endocrine and Lipid Space. Many of the Endocrinologists I interacted with were engaged in Lipid Research. A close friend of mine ( Endocrinologist ) worked at UT Southwestern under Scott Grundy ( Chief of Diabetes and Metabolism and Nutrition- the key figure in the ATP, NCEP and AHA/ACC Guidelines ). He also worked with Brown and Goldstein Nobel Laureates on LDL , the former being a hepatologist and the latter being a molecular geneticist. The list of Endocrinologist engaged in Lipid Research over the years goes on and on including Ed Bierman, John Brunzell , Alan Chait and more recently Eliot Brinton a co-author with Bhatt on the R-It paper.
Despite, the above, one chose not to engage in a personality contest with CardioMD as one finds so much value in one CardioMD brings to the Board that such statements can easily be overlooked.
What is transpiring and in motion is far bigger and way more important than minor in my mind irrelevancies.
The big picture:
Preston Mason has probably done the key research in the EPA space to elucidate how EPA is mediating it’s effects on a biochemistry, physical chemistry and measures of oxidation and inflammation. For example he has published that the unique chemical structure of EPA with 20 carbin length and 5 double bonds provides important clues to it’s unique effects. He tested different C lengths and different double bonds and the effects are significantly less. EPA with this structure is able to be positioned between Lipid membranes and infer antioxidant and membrane stabilization with decrease in cholesterol domains and cholesterol crystals which imparts plaque stabilization- further bring explored clinically by Mat Budoff in the Elaborate Trial. Furthermore, the antioxidant effects of EPA result in decrease in oxidized LDL, demonstrated in the Anchor Study, and awaiting further analysis from R-It.
DHA, on the other hand, with a 22 C length and 6 double bonds is unable , due its chemical structure, to be positioned between the Lipid membranes and thus has less antioxidant effects compared to EPA ( published by Preston Mason ).
It therefore appears likely, that Preston Mason’s research, with regard to EPA will likely be clinically validated with subsequent analyses from R-It and it is likely that the correlation with EPA and to a lesser extent oxidized LDL-C and other inflammatory markers. The key driver will probably be the incremental increase from low baseline circulating EPA levels and CV events and TG will occupy a minor role ( if any ) in this correlation but will serve more as an identifier ( target ) of at risk population and not and not a target to modify per se. With such data, it is likely that MOA via antioxidant, anti-inflammatory, plaque stabilization properties may surface. SI and IR will not appear in that discussion as such measures were not the target in either Preston Mason’s elegant research, nor in Jelis and more recently R-It. Does that mean JLs hypothesis is wrong? Absolutely not. It is a hypothesis, and being so needs further testing to be validated or invalidated.
It reminds me of JLs great Taoist story about Chan : it may be good or it may be bad. The key to this story ( IMO) is not knowing - and discovery is born out of exploration from the state of not knowing!
Final note:
We are on threshold of history in the making! The last time this occurred was with the LDL-C hypothesis and the granting of the Nobel Prize to Brown and Goldstein.
Perhaps we are approaching the dawn of another Nobel Prize with groundbreaking research on EPA during which Preston Mason, Bhatt and others may be key players in this history making occasion. I believe that we on this Board should celebrate this occasion as it unfolds and forget our personality idiosyncrasies and keep our eyes on the ball ( amazing unfolding of EPA facts ) - this is an amazing journey and the funny graphics of FFS, the clever humor of TTE, our own unyielding Hulk BB, super precise HDG, always dependable Rx Sam, Statistical AVII, super smart JL, great CardioMD, SK, North..etc etc .... this is a historic journey.... let us enjoy the ride and for a moment forget the trivia!!
Peace and thank you to All !!!
Precisely my thoughts!
Non-linear increase!
Hi Chas,
Just read your Seeking Alpha Article.
Struck me as a well written, researched and balanced article with a consistent thread of credibility and integrity compared to the Sharma article which was an antithesis of this theme !
I was previously struck by your detailed analysis of EPA and Jelis data with a bold RRR prediction prior to release of Topline results on 9/24.
I still believe if the R-It data are analyzed in the future taking into account all subjects with compliance of 4 capsules per day over ~ 5 years, I expect the RRR to more closely approximate your prior predictions!
Tip my hat ?? to you for such a courageous and thorough job on the science, particularly for an Engineer who does not apply evidence based medical science for a living!
I wouldn’t be surprised to learn that your proficiency as an engineer is in the upper tertile of your profession and deservedly so!
There is such a depth of talent on this Board that the likes of Sharma have no idea from which direction and with such utterly resounding and polished accuracy an evidence based rebuttal can be directed to them from several members of this Board.
Wishing you a good night Chas, although I cannot say the same for Sharma.
Another excellent observation AVII and Bfost.
While the N is small, as already mentioned, the CI is wide in Vital and very tight in R-It. While Black is clearly designated in Vital, the “Other” in R-It, with 11 country study, may be more heterogeneous.
Nevertheless, this is great as in recent years the question of minorities and women is always raised ( btw women nicely represented in R-It as well with a non significant interactive p value ).
Thanks for unearthing these “gems” from R-It !
Can’t wait for more analyses from banked blood samples teasing out EPA, perhaps oxidized LDL-C, and other markers and correlations with events superior to TG levels ( particularly EPA ).
Looks like Preston Mason’s research may be coming to fruition as follow-up studies on R-It unfold and MOA is more apparent as many on this Board ( JL in particular ) have previously expounded upon.
The noise around MO will simply dissipate and replaced by awe as the MOA data unfold and pleiotropic effects of EPA becomes mantra of the day. It will be Pleiotropism that explains multiple paths-physiological effects of V from MI. Stroke, CV Death, Sudden cardiac arrest, decrease in re-vascularization, unstable angina etc.
TTE, better hold on to that name, you will be in high demand and super famous !