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.......

Uh Oh......the FDA sets the bar

In an editorial from the Lancet,

Medical groups have expressed doubts about the validity, effectiveness, and clinical usefulness of direct-to-consumer genetic testing. More harm than good is done, for example, by false reassurance from unproven genetic tests or by unreliable information that could lead patients to terminate a pregnancy or seek surgery.

These are the concerns from the field and they may be valid. They may also not be valid. Let's examine each:

1. Doubts about validity-

What exactly is valid? Is valid the genotype? Is it the validity of the phenotype which the genotype is said to "predict" Is it the validity of the studies which back up the test? In the case of genotype, I would say the test is valid. In the case of the 2 others...it clearly is not.

2. Doubts about effectiveness-

Effectiveness in what? Predicition? Prevention? Guidance of therapy. On all of these counts, the doubts of effectiveness are valid.

3. Doubts of clinical usefulness-

Well, what IS clinical usefulness? Is it, the ability to derive a new use/diagnosis from a test result? Is it the ability to put into action a clinical plan to prevent or treat disease? If it is either of these, the data is not there for most DTC tests....But I also have said that clinical usefulness could just be the ability to plan for future risk or future care. In this case predisposition testing for Alzheimer or Parkinson Disease may be useful......depending on the test and its clinical evidence....To answer this question a genetic test needs:

A. A clinical study showing predictive outcome. I.E. in a prospective manner, that would be very nice. Especially if I am to tell a patient how likely they are to get this condition and when....

B. Some clinical data showing outcomes in treating patients with genetic predisposition. I.E. in the case of the BRCA1 or BRCA2 genes.

C. Some clinical data showing that an intervention on persons with a certain SNP or mutation, prevents the prior expected outcome.

Even if we had none of these things......some may say "Why not let people buy this sort of information to do with it what they wish" That is not clinically useful. It may be socially useful, but some have real questions about that as well...

In my humble opinion, this buyer beware is a very libertarian/conservative view. Which may or may not be so bad. Unless we have harm being done to citizenry.

So, is harm being done?

Some would argue no. Others argue yes.

But these data revolve around clinically valid tests. Most importantly, almost all medical societies are against DTC testing b/c of possible harm. But some argue that these motivated genetic test subjects wishing for DTC testing, self select to minimize the harm....which could be the case. But that assumes the tests are actually valid.

So what happens when the tests do not meet the criteria above? Well, no one knows the answer. But there are a ton of ethicists who are arguing against such testing. Why is this important?

Well, put simply. Medical Ethicisists most often fall along the lines of patient autonomy. In fact alot of people debate about this principle seeming to be absolute. So if most ethicists think the patient should have ultimate choice in their care, why are they against DTC testing???? Good question.

So here we are, in a position with not much data, and we won't likely have it for several years. We have ethicists who put patient autonomy first, against DTC testing. We have doctors, against DTC testing. We have government against DTC testing. Now, with the recent FDA warnings to labs promoting tests without evidence, the writing is on the wall.

“Because you do not have marketing clearance or approval from the FDA, marketing OvaSure is in violation of the law,”

That could just as easily be any other genetic test marketed to physicians or consumers. The FDA has weighed in and DTC is likely to be in its sights. Despite their detractors, the FDA is unstoppable here.

So, the answer is simple....we all have to await clinical data and trials for a clinical tool. Is that such a stretch? Is that such a bad thing? Well, it very well may be if your investors are on your case. Or if you need to pay your bills and your university salary is paltry. Or it may be if you have a mortgage whose rates are climbing? I hope you see what I am saying.....money clouds medicine, most importantly genomic medicine.

The Sherpa Says: In a time when Wall Street has a black eye from its fraud and scandal let's not let Genomic Medicine get punched too. It already has too many detractors....

Lancet and the Sherpa

After reading an editorial from the Lancet...I think that they may be reading the Sherpa. Let me know what you think. From the Lancet "Genome Wide Open"





Interpretations of the effects of human genotypes on disease are today just entering the foothills of a forbidding massif. In particular, a much richer understanding of human genetic variation is needed. However, the relentless ascent of human genomics is coinciding with growing public interest in maintaining health and participating in health-care choices. Doctors will face challenges in guiding their patients through genetic terrain strewn with difficult language and concepts, but should be optimistic that shared enthusiasm will make for surer progress.

My Blog?

To usher in the new paradigm of personalized medicine we will need to travel a perilous path. Much like the route through the Himalayas it has punished the naive and self-reliant. That is why I have dedicated my life to being a Gene Sherpa. What is a gene sherpa? The Sherpa speaks the language of the trail, he/she knows short cuts and dangerous paths to avoid. This blog is for those wishing to take the journey and those wishing to become Gene Sherpas.

Sure sounds to me like someone reads the Sherpa......

Keep Climbing,
-Steve

Save a Life!

In a recent publication in Lancet it was found that those who received chest compression only CPR actually had better outcomes if performed in the first 12 hour. It appears there is a "golden window" of 12 minutes which perfusion is much more important than oxygenation. This has turned the CPR world on its head. I am posting this here, not because there is some genetic twist. I post it to hopefully save a life or two. There have been several publications linking fear of catching a transmissible disease and decreased desire to perform CPR. Here's the good news: Compressions work just as well if not better initially.

The Gene Sherpa says: Scared of mouth to mouth? Just give compressions and call 911.