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Thanks AVII
Glad to read your response! I had the same take as you on this.
I will try to explore this further with the likes of Rebecca Juliano Ph D. or others!
Excellent points and a question,
While the 5 Pt MACE showed only a 12% non significant decrease in the Primary Prevention Cohort ( PPC ) with a significant interactive P value of 0.14 suggesting a difference in benefit between these two groups; the 3 Pt HARD MACE showed a 19% non significant decrease in the PPC with a non significant interactive p value of 0.54. The latter suggests that the benefit was similar between the two groups yet the CI in PPC crossed unity ( 0.62-1.06) .
My question AVII is whether the non significant interactive p value statistically is the driver of the interpretation that both groups benefited similarly with regard to 3 Pt/HARD MACE or whether the wider CI in PPC supersedes this interpretation and suggests that the PPC did not derive similar benefit in this HARD MACE endpoint. I have been trying to wrap my head around this one since the publication and would appreciate your scientific analysis of this. I believe accurate interpretation of the data will allow the FDA to consider the appropriate patient population to benefit from V based on R-It data.
On a separate point. I believe the fact that almost 58% of the subjects in R-It were Diabetics is highly relevant clinically.
Both Diabetics and non-Diabetics reached statistically significant benefit in the 5 Pt and 3 Pt MACE, with Diabetics trending even better with the latter ( 30% vs 20% RRR ).
While it is true that the updates in Cardiology Guidelines are separated several years apart, the ADA Standard of Care are updated annually each January and the AACE Guidelines while not annually, I believe more frequently than ACC/AHA.
I am looking forward to inclusion of V in ADA and AACE sooner than ACC/AHA. I will pose the question of inclusion of R-It data to some of my Endocrine colleagues engaged in these Guidelines when I meet with them during this year and post the response I receive to this Board !
Hi CardioMD,
It is very rare for me to have experienced such a denial of Rx and certainly not after R-It.
Prior to R-It, I have used the Lovaza label of increase in LDL-C of 49%, to counter any Insurance Lovaza alternative to V, with invariably an approval response.
I believe the uphill we are going to face in getting V prior authorization is waiting on FDA approval. Incorporation into various treatment guidelines will also make a case for standard of care. The latter two factors will make a strong case for V occupying preferred status as an add on to Statins on Insurance plans. Fibrates and Niacin don’t enter into this conversation any longer as the FDA in April 2016 retracted the indication of Fibrates or Niacin as an add on to Statins due to failed large CV outcome trials with these agents ( Accord Lipid, AIM High and HPS2 Thrive ) .
At the present time, you are in a difficult situation when in a peer to peer exchange you are faced with arrogant unyielding response reflected by blatant ignorance of the science.
What I have done in such rare occasions is have the patient make the case very vocally to the Insurance Company and the denying party in particular. Patients can become very powerful advocates particularly when his/her life is at stake ! The denial of using an add on to a Statin of a non-LDL lowering agent with 31% decrease in MI, 28% decrease in Stroke and 20% decrease in CV Mortality with no other agent ( including Fibrates, Niacin, and DHA/ EPA mixtures of Omega 3 such as Lovaza ) have ever demonstrated this LIFE SAVING benefit, is TOTALLY UNDEFENSABLE !!!!!! When a patient is armed with the strongly supporting scientific evidence he/she can often succeed by threatening to expose the Insurance Co to the media and to the respective state political representatives.
When scientific evidence in support of the patient is overwhelming and the medication is already approved by the FDA for another indication and NO OTHER non LDL reducing medication has this CV benefit, every MINUTE that passes literally poses a potential threat to the patient’s life !!!!!!
“Cardiovascular Disease accounts for an average of 1 DEATH every 38 SECONDS in the US. “ ( Heart Disease, Stroke and CVD 2018 Statistics )
The above should be a rude awakening for any reviewer who even considers denying V for CV benefit in the appropriate patient.
The science ( as all of us on this Board know ) is overwhelming and the clock is ticking .........
BB ! Any thoughts on AMGN potentially acquiring AMRN - in terms of cash on hand etc?
For BP to have two options as add on to Statins is not so bad as V is not competing with PCSK9s.
Thanks BB! Great work! Maybe worth sharing with JT??!
AnonFish,
I like your take on this !
Ok, on the “bugger all “ theme:
Here are a few phrases or clues:
Howzit;
Bunny Chow;
Fortnight;
Boot ( trunk of motor vehicle );
Petrol station ( gas station ) ;
Robot ( traffic light );
Dust bin;
Slap chips.
Can you guess the country??
STS, I wonder whether PFE has reviewed published results of Preston Mason ( Harvard ) . He postulated a mechanism why DHA and EPA have differential effects on LDL-C levels. He proposed that EPA does so by more efficiently decreasing LDL oxidation, as oxidized LDL-C is not efficiently cleared in the circulation. He measured the antioxidant properties of EPA with various Statins including Atorvastatin, Simvastatin, Rosuvastatin, Prevastatin and the Active Metabolites of Atorvastatin ( ATM ) . EPA enhanced the antioxidant properties of all the tested Statins but the GREATEST EFFECT was with ATM !! Based on this fascinating research I believe that the ideal combo pill would be with Atorvastatin with V. I am curious whether the Reduce-It steering committee are able to tease out the data comparing Atorvastatin plus V vs with the other Statins ! Over 8000 subjects ALL on Statins- should be a fairly easy analysis in my opinion!! If R-It confirms Preston Mason’s in vitro data then V plus Atorvastatin will be the go to combo in the future! I am curious what the RRR will look like with this combo in R-It !!
I know! I was brought up using it !
Haven’t heard “bugger all” expression for quite some time ! Cool !??
Hi CardioMD,
I have followed this Board for several years and somehow the members ( in my mind ) have evolved into an interesting family ( excluding those who have entered and exited in a short time ) . There are several with very in-depth knowledge of the Omega 3 space and who bring to the board their passion and particular expertise.
JL - a very intelligent an insightful mind. I have not come across a surgeon with such in depth knowledge of CV disease, inflammation, pioneer research with balloon pump etc. He does have a low patience threshold but he has the important quality of admission of an error ( rare ) if presented with facts and not opinions. You can research his prior posts, interesting and amazing to say the least.
North : a highly intelligent legal mind ( having served I believe as a Judge) first hand experience of using V and highly respected on the Board.
Sam : proficient in bringing weekly Rx updates to the board and a solid person
HD : Hungarian I believe ( only mentioning this as English not his first language) I believe his IQ is way up there ! Retired at an early age and very very detailed in DD and financial CEO/CFO type accounting knowledge and much more.
AVII : perhaps the best statistical mind on the board. Amazing simply amazing!!
VBru : another great asset
BB : the hulk who never ever gives up since the Anchor FDA fiasco years ago
SK : great asset with regard to Omega 3 and fish oils. She has contributed videos of Bill Harris widely recognized in the Omega 3 space and whom we have seen at Lipid meetings over the years
BFost : sound PCP who I believe attended the AHA and provided live updates to the Board. In addition JL and North also attended AHA.
TTE/PE : a very intelligent and humorous combo to the Board!
FFS : amazing graphics!
There have been some strange characters as well but the above is just an introduction of many strong contributors to the Board many more than 5 years.
Apologies if I left anyone out !
Overall a very colorful family in my mind !
No, an Endocrinologist. Published very little in Lipids, more in other areas - enjoyed working with Evan Stein in Cincinnati a long time ago when interest in LPa was unfolding. Have always maintained a strong interest in Lipids over the years ! Welcome to the board !
I post very intermittently though.
CadioMD : we are on the same page. Agree the NNT of 21 for the 5 point MACE and NNT of 28 for the 3 point Hard MACE with the number of zeros in the published p values is like nothing we have seen in the CV space for at least 3 decades if not more . I am still pondering if I have ever read a CV outcomes trial that has captured such consistence in statistical significance in the primary endpoint and each subsequent secondary endpoint in such a long list of pre-specified hierarchy of secondary endpoints one significant p value following the next - with only the last and final endpoint of total mortality falling short at a p value of 0.09. A landmark CV outcome trial no doubt with many subsequent papers and analyses to follow!
In terms of the first category, I found the Reduce-It publication refreshing in terms of capturing a very broad category of cardiovascular disease which is covered in detail in the Appendix of the paper - this includes prior MI, coronary artery disease defined on angiographic criteria, cerebrovascular disease including evidence of carotid artery disease and peripheral arterial disease ( PAD) based on ankle/brachial index and other evidence of PAD. This very broad category plus as you correctly mentioned the TG window of 135+ and the primary prevention population of DM plus at least one additional risk factor has allowed me to prescribe to all my patients who fit the above demographics on Statin Therapy- no Rx denials thus far. I believe that this is only the beginning of a major paradigm shift in helping our patients address the leading cause of mortality in the USA - ( more than that of all cancers combined.)
Thanks for sharing JL !!!
PS: CV Death Reduction is 20%.
Thanks, my daughter has also critiqued me about this - and I slip up in haste !
Appreciate it mm!
JL! Thanks for sharing your experience at AHA and welcome back!We all know how difficult a challenge it has been to decrease MACE beyond Statin in at risk patients and how more elusive it has been to achieve CV Death reduction even with the expensive LDL-C PCSK9s and the repeated failures of Fibrates and Niacin over the years. With that backdrop the 26 % RRR of HARD MACE, and the 20 % RRR in CV Death was breathtaking for me to read over the weekend and what really almost knocked me off my chair was the number of zeros in the P values in the PE and key SE! I understand that Deepak Bhatt was pretty deliberate as he carefully and probably proudly read off each of those zeros ( TTE was I believe SPOT ON with the number of zeros in the p value calculations particularly for the PE and key SE) . JL, please share with us what the gasps and response by the audience was like as Deepak Bhatt articulated each of those p values from PE and then SE and then showing the SS CV Death RRR ! I know I was speechless for a few seconds and then let out a loud Wow just reading this by myself ! Both the degree of RRR (20%+) across so many CVE and the strikingly significant P Values are so amazing that not only prescribing V for one’s patients but also taking V for oneself and for family and friends will soon be a norm by Healthcare providers ! The magnitude of this in our lifetime has still not really sunk in !! JL, a cool poetic description in typical JL style for the Board would be appreciated to capture the audience response as Bhatt pointed to each and every zero in those P values! A second by second commentary would be appreciated to get a sense of the energy in the crowd and also Bhatt’s demeanor when he read out the number of zeros !! I am sure TTE in his Santa outfit would have received acknowledgement as all the zeros popped on the screen, if he was among the Attendees!! This is going to be life changing for millions and millions ( yes, at least the same number of zeros as in the P Values) !! I think there should be a special article on P Values in Reduce-It! What do think about that TTE ?
Oops! I meant Rebecca Juliano and not Dr Miller in my prior post.
AVII, I have the same experience as HDG when reading your message on my iPhone IHUB App. When on my laptop on Google Chrome your linked images are clearly there. Of interest, your investorvillage link on the IPhone worked !
Thanks for posting the Excellent Graph from 14 Statin Trials and your insert of plotting the Placebo R-It LDL-C change which equates to ~3.5% in Major Vascular Events ( a figure similar to what Deepak Bhatt mentioned in a now frequently viewed Youtube clip which you kindly shared with the Board yesterday) .
Another point worth mentioning is that for several years when I shared the Marine and Anchor data with colleagues, it was predominantly the Cardiologists who would point out the DECREASE in HDL-C in the V arm and whether this may have an adverse implication in CV Risk in those taking V. The order of decrease in HDL-C was ~5%, and the final comment would be that the Reduce-It CV Outcomes Trial is ongoing and should answer whether this degree of HDL-C decrease translates into any meaningful INCREASE in CVE in the V arm. Interestingly while several Cardiologists ( and others with their own agenda) correctly pointed out the potential effect of a increase in LDL-C in R-It in the Placebo Arm, there was an interesting SILENCE regarding the corresponding INCREASE in HDL-C in the Placebo Arm ( or conversely a DECREASE HDL-C in the V Arm ) in R-It. Cherry picking would be an appropriate description of such selective behavior. No mention from any of the critics on the degree of HDL-C increase negating some of the Increase in LDL-C in the Placebo Arm was mentioned. The only occasion I recall this being mentioned was by Dr Miller during the 7.15 PM CC last night. In my opinion, she did a great job presenting the data and some of the subtle nuances. This CC is worth a listen ( CC replay available ) by those Board Members who could not connect during the Live presentation.
PS : I like 25%RRR pre-AHA 11/10 or 26%RRR post AHA on your CAT. I am sure many Board Members would be happy to assist with the paint job!
Thanks again for your Outstanding Scientific contributions to the Board!
VuBru: Very valid points indeed. Thanks . As R-It is largely a Sec Prevention population and therefore the label will probably apply to address Residual CV beyond Statins in this population with the Diabetic subgroup perhaps being piggy backed in some way (if stellar) . I do however believe that if BOTH Primary and Secondary populations garner benefit, I foresee that the Primary subgroup data, while probably not being specifically recognized in the label itself still potentially being able to be shared with Providers with the IA win as long as the shared data are “truthful and not misleading “. This is in my opinion a significant plus. It is quite interesting that although GSK despite it’s size did not have the foresight to pioneer a IA challenge with the FDA. I believe Amarin was probably the first to challenge the FDA with an amazing legal team and being successful with a IA win. GSK did however conduct a trial similar to Anchor which they called the COMBOS Trial ( Lovaza added to Simvastatin treated patients with TG 200-499) . GSK was unsuccessful in gaining FDA approval for the Combos population and never undertook a CV Outcomes Trial which was the appropriate next step due to the fact that time was running out for the Lovaza patent. However, interestingly, the Combos Data was allowed to be included in the Lovaza prescribing information. The GSK Reps found creative ways in sharing the Combos Data with Providers so much so that, in almost a subliminal manner, Providers began to prescribe Lovaza for TG 200+ patients despite the fact that the indication was only for TG 500+. I believe that the majority of Lovaza prescriptions that accumulated were actually for the Combos population rather than the narrow TG 500+ population.
Amarin has this great IA win in it’s pocket and I believe also has an additional legal accommodation of obtaining 2 additional indications per year - I cannot recall the specifics of this legal verbiage accurately at this moment but I am sure that JL, BB, or HDG, or some of the more seasoned Board Members, may have record of the specifics somewhere. With the wealth of data presented at AHA and in subsequent publications I believe the IA win may allow greater visibility/transparency of the SE, TE, subgroups etc than would have been possible without the IA win. “Truthful and not misleading “ may be the precise IA win that Amarin has brilliantly secured to share way more data than would have otherwise possible after AHA and more importantly after publication in a peer reviewed Journal. There are other areas of brilliance such as securing a wealth of patents, the deal struck with Teva, collaboration with Mochida and a Brilliant R-It study design to capture TG not only in the Anchor population (200-499) but TG of 150+ and thus even snatching the 150-199 TG population as well. It appears that they hardly missed a step. For such a small Company patiently planning and diligently making each calculated move, never losing sight of its long term goal and overcoming challenges and battles along the way that Big Pharma such as GSK could not have even imagined, speaks volumes of an amazing journey with a well deserved and almost dreamlike 25% RRR and with more to come.
JL:
I see two important components in that statement:
Firstly that improvement in Residual CV risk is beyond LDL control, the current modalities to address the latter include Statins, PCSK9 inhibitors and to a lesser degree Ezetimibe. Hence V targets this Residual CV Risk in a novel way ( not targeting LDL-C) and not specifically addressing TG per se. Thus opening the discussion for its Pleiotropic properties and TG in this population serves not as a target modulate but merely is a marker to identify underlying atherosclerosis and enhanced CV Risk. Inflammation is Key in the pathophysiology of the underlying CV disease and well supported by the various biomarkers which have surfaced in previous publications and will likely be emphasized in the R-It publication and also at AHA. This first point is well known to many on the board and you JL have thoroughly expounded on this well before most of the Physicians I know had even thought or read about it.
The second point however, in my mind was subtly hidden in the statement that was quoted by AVII, and the word “both” between Primary and Secondary prompts one to consider ( as AVII correctly suggests ) that perhaps we are going to hear at AHA ( and the publication to follow) that despite R-It comprising predominantly of a Secondary Prevention population the word “both” suggests that perhaps we are going to learn from R-It a benefit for BOTH Secondary and Primary prevention. As Primary Prevention captures a larger population both in the USA and globally, with this “hint “ the potential market for V has magnified considerably. If this “hint” materializes to a reality at AHA, the Pharma Industry and Analysts will have to quickly recalculate and revise their more modest projections of the population that V may potentially reach out to. I must confess that I did not catch the word “both” in the sentence quoted by AVII until AVII posted it. It does boggle the mind of the potential of V both Primary and Secondary apply. This is besides other large populations such as Diabetes potentially garnering benefit. In addition it is also likely that tertiles of TG levels may be presented at AHA which may provide further stratification of CV Risk. This makes one think back to data from Bay Area Cardiologist Ron Krauss who demonstrated years ago that the more atherogenic Pattern B LDL Phenotype starts to manifest when TG increase not above 150 mg/d but above 100 mg/dL, when increasing waist circumference and features of Metabolic Syndrome begin to manifest. It is likely that inflammatory biomarkers may be elevated in the 100-149 TG window as well , potentially providing future use of V in this population as well. I may bring this point up when I meet Matt Budoff in the near future as a population for future study. All in all AHA is building up to be quite something with hopefully numerous publications to follow in swift succession thereafter.
Interesting observation AVII.
While Jelis had a predominantly Primary Prevention subjects and R-It the reverse, your astute observation in picking up both Primary and Secondary Populations in that statement is very meaningful in terms of V potentially having a much broader application. Throw this in with the Diabetes subgroup analysis, MACE Hard SE and Mortality data, and the AHA audience may be in for treat for the ages!
Excellent point AVII, TTE and VuBru.
I believe another factor to consider is the challenge of compliance with 2 capsules BID for approximately 5 years. An analysis of subjects who adhered to the treatment may perhaps show RRR close to 40%, in line with the figure in Prove-It Timi 22 and RWE and also in line with I believe Chas’s ( one of our Board Members) detailed prediction months ago. I believe it is a matter of time when we have RWE with V which will probably be well North of 25% sealing the interest of both Insurance Companies and Health Care Providers and also mirroring first hand experience by North, a highly respected member of this Board. Apologies North, I could not resist the punn temptation ! All expressed in the spirit of healthy exchange, Sir.
Thanks AVII. Good point regarding MI.
I believe that the magnitude of the RRR ( similar to the dawn of Statins) and potential for SS reduction in CV Death bode well for Reduce-It to be a game changer in the CV space on 11/10. The other SE and sub-groups including Type 2 DM may be worthy of providing a pleasant surprise!
AVII; Thanks and a question:
Interesting presentation of Fourier with PE, Key SE and FDA CV indication in label. The PE had 5 components MI, Stroke, CV Death, Hospitalization for UA, and Coronary Revascularization. The Key SE ( Hard MACE : CV Death, MI, Stroke ) p<0.001.
In terms of Hierarchy of SE, the next following HARD MACE was CV Death with a non significant p value of 0.62. The P values of subsequent individual SE after CV Death were reported but just exploratory based on Hierarchical design .
Of interest the exploratory p values of individual SE after CV Death were as follows:
MI : p <0.001;
Stroke : p = 0.01;
Coronary revascularization : P < 0.001;
Hospitalization for UA: p=0.89.
As you stated the CV indication in the label is for prevention of MI, Stroke or Coronary Revascularization .
My question to you is whether there are similar precedents where the FDA examines the PE, Key SE ( Hard MACE ) and individual SE and then selects individual SE to be incorporated in the label which are not precisely similar to the components in the PE of the study or the Key SE of the study. In this context did the “exploratory” p values perhaps play a role in qualifying MI, Stroke, and Coronary Revascularization for the CV indication in the label but NOT Hospitalization for UA. It appears to me that perhaps the exploratory p values may have had some weight in the components of the label or is there perhaps another explanation. If there are such precedents I would be grateful if you could kindly share these at your convenience as this may perhaps be relevant in evaluation of the PE, Hard MACE, and other individual SE in Reduce-It when these surface on 11/10. Always appreciate your very measured and in depth contributions.
Thanks North!
Mmmm!! TTE!! You know what I like about you is a sense of harmony and balance - that allow you not only to express your innate intelligence but also have a spontaneous and refreshing sense of humor. These are in my mind the true qualities of a scientific mind that can freely explore any question without the dark screen of agenda obscuring discovery. A joy for one who lives such a life and a sad tragedy for another choosing not to.
TTE: Let me see if I have this right! If V is NOT “Pleiotropic Extraordinaire “ (PE ) in mediating it’s anti-inflammatory properties with a 25% RRR in Reduce-It ( bearing in mind that such anti-inflammatory properties have been supported by a Plethora of both In Vitro and In Vivo Studies where Mineral Oil was NOT even present as a comparator ) then is it being implied that Mineral Oil has become the newly discovered hot Fiery Pro-Inflammatory agent on the planet which has magically not only erased the effects of V ( an innocent bystander in Reduce-It where V has just been tagging along for the ride as the disguised Placebo Arm must be truthful and not misleading by being fully transparent ) but even more magically INVISIBLY erasing the anti-inflammatory effects of V both In Vitro and In Vivo Studies where Mineral Oil was not even present - these include architecture of fibrous cap of plaques reviewed by Mattt Budoff, Crystal Domain architecture by Preston Mason etc etc ! Wow ! “ Mineral Oil “ must then be until now been THE under the radar fiery Pro-Inflammatory INVISIBLE stealth threat to the human species masking as an innocent GI friendly nudging agent and having effects in inflammatory processes without even being physically there - simply magical !!! Come on TTE, as President of the Board and Savior of Mankind you owe it to us to be truthful and not misleading in being the Ultimate Sherlock in connecting the dots of this greasy and oily puzzle!!
Breaking News !! Mineral Oil Raises CVE by 25% p<0.00000001 !!! ( Seven zeros right TTE ) . Hot and burning off the Press!! Hmmmm can’t wait for Mineral Oil SE !! If CV Mortality and Total Mortality are highly significant then we have found the answer to simply erase the present human population and recycle with a fresh new start!!!! The greatest solution to recycle not only the content of your gastrointestinal tract but the entire sick and constipated human species !! Wow Wow !!! I am simply “burning” with excitement for November 10 - must fight my constipated constitution and hold off using even a single DROP of potentially LETHAL Mineral Oil until then - !!! Don’t worry TTE! I do know Matt Budoff personally ( have met him at numerous meetings over the years ) and will give him the heads up in calling off The Evaporate Trial ( which is exploring the effects of V of Plaque Progression and markers of inflammation and Lipid Biomarkers) now that the secrets of Mineral Oil have slipped out ! I will gently tell Matt to simply have a slug of Mineral Oil and call it a day !!! In the meantime TTE just take care of connecting the dots of the slippery puzzle and make sure you don’t get a single drop of the potentially lethal stuff on your big hands ! Did I just say big hands !! While you are at it, might as well figure out how your hands got bigger- while taking V ! TTE ! I think you have your hands full with this one ! Good luck !!
TTE ! One thing I am certain of is that you are never short of ideas or humor and that makes you worthy of having the title of “President “ of this board ! I believe that “Topline25RRR” will not only remind AVII of the date of the memorable PARADIGM SHIFT but also blend with his in-depth flare for the “Scientific Method” for which he occupies in my opinion the NUMERO 1 position on the board although you often prod very very close to that position as well TTE! Your suggestion pertaining to pleiotropism speaks to the MOA of V and also compliments AVII but I am not sure he is biting strongly on it as yet !!
How about : “Topline25RRR”
as the name for your Hobie successor. It kinda suits you !
Agree JL ! Prior to Topline I was prescribing V for the Marine and Anchor population, TGs of 200+. Now with Reduce-It population showing a 25% RRR, I am also capturing the 150-199 TG window of which a large proportion as you know are Diabetics or those manifesting Insulin Resistance with Metabolic Syndrome. I have been writing about 3 new V Rx per day !
HDG: Question. If any BP submits a BO offer to Amarin, is the Co obliged to make this public or if JT has no interest he may choose to decline such offer and not make such BO offer public. What are the prevailing rules ? Thanks.
Good points TTE. I just re-checked the list of SE and CV Death precedes Unstable Angina (UA) in concordance with your opinion and JTs statement “robust across multiple SE” - this puts CV Death in my mind as likely to be statistically significant particularly as it precedes UA on the SE list where UA may well reach statistical significance. The last item on the SE list is Total Mortality and it is possible in my mind that this p value may perhaps not make it. On the other hand wouldn’t it be something if ALL SE are statistically significant and JT in his conservative way has been concealing his excitement by mentioning : “wait for AHA” That will make Nov 10 at AHA = Breaking News for the ages !
VuBru, thanks for your helpful comments . I believe it was TTE who had done some detailed calculations on the actual p value of Reduce-It in the order of 0.00000001. Should not this magnitude of p value and the 25% RRR of the PE in Reduce-It give more wiggle room for significance in SE if one looks at the more modest PCSK9 trial data as a comparison. I do not do Statistics for my day job nor even as a hobby, but I believe you, AVII, TTE and others on this board are able to tease such figures and predictions in Hierarchy of SE quite effortlessly with a more in depth background in Statistics.
AVII, VBru, TTF, JL, North and others. Some perspective on PCSK9s:
1) Fourier Trial :
PE: MACE: HR 0.85; p<0.001.
SE: CV Death : HR 1.05; p=0.62.
SE : Death any Cause: HR 1.04; p=0.54
2) Odyssey Trial;
PE: MACE : HR 0.85; P=0.0003
SE : CHD Death : HR 0.92; p=0.38.
SE: All Cause Death: HR 0.85; Nominal p value* Hierarchical Testing : p=0.026*
The Cardiology community ( as well as the Insurance Industry) is fully aware of the relative modest 15% PE benefit on top of Statins of the expensive PCSK9s and the lack of Mortality benefit. We are going to be all ears soaking in the string of SE and TE of Reduce-It at AHA and if the Mortality benefits in the Hierarchy of Reduce-It SE are significant ( not just nominally) the news will be mind blowing to say the least.
Appreciate any comments and perspectives from AVII, VBru, TTE, JL, North, HD and others in terms of such SE Hierarchical test results.
JL and others ! You may find this of interest. I have been writing V Rx for any patient whose TG are >150 with CV Risk .
The Prior Authorization questions are very simple:
1) Does the patient have a Diagnosis of Hypertriglyceridemia; Y/N
2) Does the patient have a TG level of <500; ( >500 means of course automatic approval with no further questions asked);
3) Is the patient on a Statin?
4) Has the patient had an inadequate response to Fibrates or Niacin or is the patient not a candidate for these therapies? A Yes reply to questions 1- 4 is met with immediate approval!
Now get this ( JL would enjoy this ) - the duration of the approval is INDEFINITELY!
I previously used to obtain only a 12 month prior authorization for all my PA prescriptions! This is the first INDEFINITE approval! I will need to track other V PA moving forward!
Excellent discussion AVII, TTF, BB et al. It is a known fact that death from CVD in the USA exceeds death from ALL cancers combined. Therefore, if Reduce-It shows significant decrease in Mortality, this would make such a case difficult to argue against. I can visualize BB thinking that this would be a slam dunk and simply just give in to a prior suggestion from a member of this board and become the newly appointed head of the FDA!
HD: Excellent recommendation.
AVII and VBru; I recall the first CV outcome trial with a Type 2 Diabetic agent to have a significant impact in MACE was the Empareg Trial presented at EASD on Thursday September 17, 2015. It was clearly BREAKING news, being the first Diabetes agent crossing, until then, the unattainable threshold of significantly reducing CVE in Type 2 Diabetes. The 38% decrease in mortality was earthshaking to say the least. There was standing room only at that presentation with Breaking News being the theme not only for that day but for many many months beyond that unforgettable date. There was an audible buzz amongst thought leaders in Diabetes and CV Disease. Cardiologist had to be trained and educated on how to use a Diabetes medication in reducing CVE in their patient population! Total shift in treatment algorithms!! On that same day ( Thursday) of the Breaking News presentation at EASD, the Empareg paper was published in the NEJM 9/17/2015 - well orchestrated by the presenters to select the date of the presentation to coincide with Thursday NEJM publication day. I recall thoroughly reading the article online on that very evening! It is my opinion that as the Reduce-It presentation on November 10 at AHA is on a Saturday, the earliest date to get a NEJM publication on Reduce It would be the following Thursday - unless an alternate Journal is selected, which I doubt. I do believe that with the Reduce-It presentation at AHA there will again be standing room only with the packed audience eagerly soaking in the data which will provide a new paradigm in treating Residual CV risk beyond Statins and with new Guidelines swift in adopting these data after the publication.
JL! Do we have your OK ??