Ok, Spam Botted! Prasugrel PLUS 2C19 PM has better outcome.

Alright, so I just found out that I posted a spam bot post. Not from a nice student named Ashley.

Instead what I will post is a subgroup analysis of TRITON TIMI 38. The subgroup analysis? 2C19 PMs and Prasugrel.

Great clinical question-Did the PMs (poor metabolizers) on Prasugrel fare better than the PMs on Plavix.

The obvious answer:
Duh, of course yes.

But Always we need some science and statistics here.

Individuals with a CYP2C19 reduced-metabolizer genotype were estimated to have a substantial reduction in the risk of the composite primary outcome (cardiovascular death, myocardial infarction or stroke) with prasugrel compared to clopidogrel (relative risk 0.57; 95% confidence interval [CI], 0.39 to 0.83).

Ok, so we should screen for PMs? Probably.

What about every other result?

What about the EMs?

For CYP2C19 extensive-metabolizers (EM) ( approximately 70% of the population), however, the composite outcome risks with prasugrel and clopidogrel were not substantially different (relative risk 0.98; 95% CI, 0.80 to 1.20).

The Sherpa Says: We should AT LEAST be identifying the PMs and placing them on Prasugrel. This subgroup analysis shows increased risk while on Plavix. Primum Non Nocere.

Congratulations Generation Health. Nice pick up!

Is it any surprise that insurance companies have no clue what the hell is going on with genetic testing?



You see, there are a set of ICD9 codes that can mean 2C19 testing or hepatitis pcr........



The coding system doesn't allow the companies to run their algorithms accurately......



Insurers have no clue which is which and they are getting banged out for these tests.



Don't believe me, just take a look at what United has done with their BRCA testing (which BTW has their own codes)



"By instituting a prior notification policy and placing Myriad in charge of determining which patients get tested, United Healthcare can monitor more closely which of its policy holders are receiving testing on BRACAnalysis."



Add in the SGO guidelines which suggest a 5% BRCA carrier risk may be worthwhile and you can see why the companies are looking to stop the carnage or testing overuse.



Myriad on the other hand would beg to differ. They see years of under utilization as something to combat. And they are very successful at it, just check out MYGN.



The answer is somewhere in the middle. What is a responsible insurance company to do?



Answer: Generation Health.



What happens when genetic testing costs less than 100 bucks? Well, then maybe Generation Health will need to speak with me regarding a diversification company we are working on.....



With other PBM companies actively looking at new automated strategies for GBM (not glioblastoma multiforme) Generation Health is an interesting play.



I remember speaking with a certain player who also was involved with the DTC companies, who agreed with me. DTC is a bull$h!t play, benefits management of real testing, hyperlipids, HCM, etc are where the puck will be......From the Genome Web article (HT Turna Ray)



"The partnership will also “allow the companies to explore future programs in the medical diagnostics arena to encourage appropriate and cost-effective testing for certain hereditary diseases, and eliminate unnecessary testing where evidence for clinical validity and utility is lacking,” the collaboration partners said in a statement. "



We talked about this for some time (unnamed MD and myself) and then.....radio silence.......Only to show up with funding and some small hits.



They chose genetic counselors instead of my band of geneticists......



These guys are moving in the right direction. The industry is shaping up and guess what the killer app for genetic testing is?????



That's right, actual, honest, regulated medical testing........ Go figure.



Now, who gets what, how is it paid for, how is it used?



These are the questions that will need to be solved.



Until of course the accuracy and cost of a genome is less than 500 USD Which could be quite a while.



Meaning, Generation Health has about 10 years of life as the company it is right now. Not bad.



Imagine saving insurers millions per year, then taking 10-20% of those savings......... per year CVS/Caremark is a great partner and now owner/investor.........A very strategic investment.



My guess is that the DTC companies will fall in line or perish. Then labs will have to start marketing better, offer faster turnaround times and there will be "preferred" lab status.....per insurer.



Basically creating a super confusing land mine for physicians and patients. Just like radiology, just like surgery, just like chemo, just like......medicines



The Sherpa Says: Finally, corporations and investors are figuring out what IS important. Staying alive and having your medications work!!

Pharmacogenetic Indication for a Medication?

That's one way to market the newest medication to prevent stroke, heart attack or stent thrombosis.

Wha? Yes, I mean, Prasugrel otherwise known as Effient is FDA approved for use in these patients.

But one thing I was thinking is that, since the FDA put on the insert of Plavix that 2C19 testing may be useful to identify people who will not respond to Plavix (generic Clopidogrel)

Perhaps, the marketing geniuses over at Eli Lilly could use this as an FDA suggestion that these 2C19 people may be better off with Prasugrel.

Yes, it would be one of the most brilliant ways to market pharmacogenomics. I can only imagine the DTC genomics companies salivating over this "We offer the 2C19, test. Act now, save your life." Technically, It actually could. Yes, all the stops would be pulled out and it could potentially save the DTC genomics companies.

You may be asking yourself, "The DTC companies need saving?"

Yes, they do. Face facts, Research revolution is a flop, nowhere near 1000 people per study. Funny how people don't trust google or anyone without proper research accreditation.

Navi is slashing costs and they have a CEO who is the master of running wastelands (i.e. companies where all the bad assets of a VC firm go)
DeCodeMe.....huh?
Pathway and Tru have no marketing budgets and no real scientific staff.......... Seriously here. WTF?

But, if they could get one big hit from Lilly shoving billions into this PGx marketing campaign, they could be ok. Otherwise, I am afraid, they are lost.

For Lilly it would be a huge win too. Why? Imagine being able to pull a full 1/3rd of all patients taking Plavix off and switching them to Effient/Prasugrel. They could, they really, really could.

So now that I have you attention. The big question is , when will Eli Lilly do this? My guess, in the fall.

Mark my words, they WILL DO THIS and it WILL SAVE companies like 23andSergey and Navi. If of course they offer the test. LabCorp, Genelex and Quest all offer the test now.

But here's the rub, if they offer this and say it is used to make a clinical decision, then they will be a part of the healthcare industry......... Oops, forgot to mention that before. Survive and take regulations or Die..........

The Sherpa Says: This would be the most brilliant marketing campaign in the world, Personalized Medicine awareness would be worldwide, and Pharmacogenomics would hit the stage in a major, major way....Thanks Lilly, call me to orchestrate your campaign.....

Great Job Mike! 2C19 meets the grade!

I was flipping through the internal medicine news yesterday when I saw a colleague. Mike Murray, Clinical Chief up at the Brigham who had given me some good advice re: being a fellow and academia......

He and a couple other internal medicine geneticists write a column called "Genetics in Your Practice"

Which is a welcome addition to what my wife and I (Both Internists) believe is one of the best print publications out there for keeping ahead of the curve with IM and subspecialties....

Well,
Mike wrote about Plavix, which, as you know, I have been all over since the studies came out in January showing significant differences in outcomes clinically with patients who cannot activate Plavix. Why was I all over it? Because it had met some criteria which I think will define what a good PGx test is......

I have as of yet failed to detail precisely what these criteria are.....It just so happens, Mike did a brilliant job of it.....So without further ado. Dr. Mike Murray, Internists, ID specialist AND geneticist defining the criteria....

From Internal Medicine News

So, what will bring a breakthrough application in pharmacogenetics? I believe that a true breakthrough into the mainstream will occur when the gene-drug pair has many or all of these characteristics:

▸ A widely used drug. There are currently some excellent examples of gene-drug pairs as models for the clinical application of pharmacogenetics; however, they happen to be with drugs used by only a small number of subspecialists. A true breakthrough application will need to be a widely used medication.

▸ An “essential” drug. Although we may eventually get to pharmacogenetics testing for almost all medications, a true breakthrough application will not be for a drug for which the application is usually elective (e.g., onychomycosis therapy) or for a drug that has equivalent substitutes inside or outside of the class (e.g., a diuretic for hypertension).

▸ Potentially severe consequences from use of the drug without pharmacogenetics guidance. The motivation for using a pharmacogenetics approach is mainly safety or efficacy. The breakthrough application will need to help the prescriber avoid morbidity or mortality associated with side effects or ineffective treatment.

▸ A narrow therapeutic window. Aminoglycoside antibiotics are classic examples of drugs with a narrow therapeutic window, where underdosing can lead to disease progression and overdosing can cause adverse effects.

▸ Pharmacoeconomic advantage. The application of new technology to guide gene-drug decision making will be more attractive for clinical uptake in instances where it offers cost savings.

▸ Straightforward genetic interpretation. Much of current genetic testing deals with complex interpretations of sequence data where variants unique to the individual patient have to be judged as causative, noncausative, or of unknown significance. In 2009 the most straightforward diagnostic genetic testing is based on screening for common variants that confer increased relative risk.

▸ Validated significance of gene-drug pair. There will always be varied levels of confidence in any data set; however, replication of significant correlation in more than one large, well-designed study will be the most likely to be associated with rapid clinical uptake.

This is precisely what Plavix is......And it is precisely why it will lead personalized medicine this year.......Not genome scans, not whole genomes, Plavix pharmacogenomics...... Mike, yet again, you have crystallized criteria which I often find nebulous......

The Sherpa Says: If we judge all tests by this criteria we would be better off.......Imagine how many less tests would be ordered. Bad for business, great for medicine......

Duh!!! For at least 5 years we "knew" this!! PPIs and 2C19

In case you missed my further rants about how everyone on Plavix should be tested for 2C19 polymorphisms, often splice site changes, which could hinder the effect of plavix......Now a big fat , No Duh....comes out in the Journal of the American Medical Association.

Let me lay the ground work.........

Plavix, one of the top 3 medications in the world

1. Prescribed to prevent a second heart attack or stroke


2. Prescribed to prevent a clot forming in a coronary artery stent, which one often receives after having a heart attack


3. Given in patients with PAD

It turns out that in order for this medication to work it needs to be converted from Plavix into its active metabolite. This type of medication is called a Pro-Drug. There are others like this, including tamoxifen and codeine.

Well, the enzyme which converts Plavix to its active metabolite is called CYP 2C19. We have known this since 2000. A professor of mine actually published on this back then. We even knew about so called "Plavix resistance" .

We know theorize that Plavix resistance is mainly due to polymorphisms in CYP 2C19. This has been studied since 2000, but only recently came to major light with articles in Lancet, New England Journal of Medicine......and my rants on this Blog and in Lectures at Yale and Affiliated Hospitals....

Now........the fly in the ointment....

Proton Pump Inhibitors(PPIs) like Prilosec and Protonix........Are available over the counter since they are so "benign"......

Well, we have known and studied since 1997 that Prilosec inhibited 2C19's ability to biotransform other medications.

So what about allof the people taking BOTH Plavix and PPIs? Let me guess.... the results are like the data in 1997!!!!! That patients receiving both medications have little Plavix effect and decreased platelet inhibition.

Well, that was shown in 2006 and even some preliminary data in 2004.

So one has to ask, well why haven't we put anything on the label? Why haven't their been huge warnings....even more so....how many people are on Plavix and PPIs? The pharma companies know.......how come they haven't warned people pre-emptively that there "May be a problem"

The FDA always asks how much evidence is enough.....but now with the study just published in JAMA it is painfully clear.....we have missed the boat by requiring TOO MUCH PROOF!!

What does the study say? Those who are on Plavix and Prilosec are 27% more likely to have a recurrent hospitalization or DEATH from acute coronary syndromes than those NOT ON THIS COMBINATION!!!

AND, 2 of 3 people in this study on Plavix......were ALSO on Prilosec!!!!

This study was a retrospective study which does have limitations, but has me asking why do we have 3 years of data on this combo 2003-2006, when we knew that there may have been a problem back in 2000????

Why didn't we do a better post market analysis?

What's even worse......people advocating pharmacogenomics are getting push back from lazy clinicians who are asking for randomized double blinded studies to PROVE this problem.....

But here's what they don't know.....the pharmacology literature is robust with Pgx data, just as it was with PPI 2C19 inhibition data....Too bad doctors don't read pharmacology literature....

Anecdotally, when I was a resident, I pulled all of my patients off PPIs that were on Plavix. What did I do? I did a med reconciliation and became aware of the possible interaction.....In this case it was NO BIG DEAL to put them on H2 blockers instead......

Primum Non Nocere.......not PRIMUM RANDOM DOUBLE BLINDUM.....

This just pisses me off.........9 years to come to clinical light........That is a damn shame, That may also happen with Prasugrel....

The Sherpa Says: Why do we as physicians wait for a large organization to say stop, when we have the education to figure out from the literature when we should have stopped? Or for that matter, when we should have started......the burden of evidence has been overcome here.....Unlike SNP Scans.......