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.......

A little story

I want to wish everyone in the US a happy 4th of July. The fateful day took tremendous amounts of courage to stand up against status quo. Our Founding Fathers risked life and limb of not only themselves, but also their families. They would not stand for the tyranny and taxation that was levied upon them.

Too bad our medical community isn't as courageous.

I want to tell you a story. I was a resident at the time.

JT was a 16 year old boy who had just been diagnosed with ulcerative colitis. It is an inflammatory condition of the bowel. He had been having episodes of horrible diarrhea and when he received the diagnosis he was started on a medication called 6-MP. If you must know, I was training in Internal Medicine at the time. Prior to this I trained in pediatrics......You see, in pediatrics before we start this medication, we do a genetic test.

6-MP can cause horrible suppression of your immune system and bone marrow. It actually has been used as a chemotherapy in the past. We do this genetic test as essential standard of care in pediatrics. Unfortunately, that was not the case in Adult Medicine. You see, there are adult GI doctors still starting this medication and watching to see if the toxins build up and case a drop in the white blood cells....(Sound Familiar?)

Well, JT went home on 6-MP and was doing great. In fact the week before his birthday he had no symptoms at all. He even skipped his check up and lab draw. But something terrible was going on in JT's body. On his birthday, he went to the bathroom and collapsed. He was unable to get up and was so weak he couldn't call for help. Luckily he had his cell phone on him and while he was in the upstairs bathroom he called his home phone.

His father picked up. "Help dad! I can't get up! I am in the upstairs bathroom"

His father raced up stairs and brought him into the ED. That's where I come in. I saw that JT was just started on this medication a little under a month ago. I ordered some labs and started JT on antibiotics. Based on the fact that he looked white as a ghost, I knew.....he had bone marrow and immune suppression. My lab values came back confirming the diagnosis. JT had the worst side effect from this medication.

While in the ICU/hospital (For 2 weeks and over 30,000 USD in charges) he fought of a bacterial infection in his blood. He received multiple units of blood and injections to stimulate his bone marrow. The Adult GI doctor THEN sent off the genetic test. Guess what? He was a NON-metabolizer of this horrible medication. That's why he did so poorly.

I recently asked my friend (Head of GI at a very respectable hospital) why they ONLY now are recommending genetic testing in Adults. He said, there was "very little evidence behind dosing patients according to genotype". Huh????? I asked if now there existed an algorithm to adjust dosing in poor and intermediate metabolizers. He said "NO"

Yet now, genetic testing is standard of care for dosing 6-MP.

So I ask you.

With an algorithm in place for Warfarin, FDA recs on the label, an FDA approved test and established evidence behind the basis of genetic testing, why do the adult doctors demand "MORE EVIDENCE"? When they obviously can see the aftermath of hundreds of JTs.... Or maybe they can't see the aftermath?

I guess just a few more thousand deaths from Warfarin toxicity need to happen.............

The Sherpa Says:

Sometimes, you just have to err on the side of protecting the patient. With GINA in place, adult doctors everywhere have nowhere to hide when it comes to this. Just ask my colleague, Gary Marchant JD, PhD............. He stated it explicitly in our last CliniCast(TM)

Clinical Utility? Now all you doubters look foolish!

I just wanted to let everyone know again about the website for coumadin dosing according to genotype. This algorithm is available on the web at warfarindosing.org

This algorithm is going to be published tomorrow in the journal Blood.

For all you hater Internists and Clinicians who refused to learn genetics or maybe never had genetics......Welcome to the 21st Century, Read the name tag. You're in my world now Grandma!

Chemotherapy Toxicity Genes

Imagine if you could predict who would get the nasty side effects of chemotherapy before giving it. We could then taper the chemotherapy giving less of a dose and achieve the same response. Well, the first part of that dream is here today. At St Jude Children's Research Hospital they have been actively investigating pharmacogenomics and chemotherapy. In a study to be released in the May 15th edition of Blood we have just that.

The major findings include

• During the induction phase Vitamin D Receptor polymorphisms were linked with gastrointesinal symptoms (diarrhea, nausea, vomiting) 6.85 times more likely.
• Polymorphisms in Cytochrome p450-Family 3-subfamily A-number 5, were almost 5 times more likely to have infections and Neurotoxicity
• During consolidation phase the Reduce Folate Carrier polymorphism led to the GI side effects with a 10.4 odds ratio.
• UGT1a1 polymorphisms led to jaundice as well as reduced clearance of an agent called methotrexate (a chemo drug) perhaps leading to increased toxicity as well

This is a major study, that has had some replication in one gene or another. But the compiling of these polymorphisms has not been done. Likely we will need one more round of evaluation. But after that...we could have a pharmacogenomic test for side effects.

The Gene Sherpa says: This is great, but how do we adjust the chemo to avoid these reactions. We will likely need an adjustment scale based on polymorphisms. AKA Personalized Medicine! I am certain St Jude's has this in the works. Let's keep our eyes peeled :)