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Plavix Failure and Patient Non-Compliance? I don't think so Jeptha.

Posted Dec 25 2008 6:53am

A colleague of mine Jeptha up here at Yale told me....people fail plavix because they don't take it. He said this in response to a patient we had taken care of who had just received a stent for his heart attack. This situation is actually very common in clinical practice. I told him about 2 years ago now "No, people don't metabolize it into active compounds and may have platelet polymorphisms that lead to its ineffectiveness"

I said this based on preliminary data in 2006 and my clinical identification of several patients with in-stent thrombosis who are not exactly the non-compliant types......

Turns out....I may be right.

Recently I was talking with my wife (who is also an Internist) and I said "What came in the mail?"

She said "Oh, nothing. Just the NEJM, but there wasn't anything good in it"

Just today I was able to read it online. Holy crap!!! Nothing Good. My wife actually said this...But then I realized that the articles were online first!

Well, In the NEJM they studied CYP 2C19 polymorphisms and risk for cardiovascular events. In addition, they brilliantly assessed plasma levels of active metabolite. The study breakdown and then the results


We tested the association between functional genetic variants in CYP genes, plasma
concentrations of active drug metabolite, and platelet inhibition in response to clopidogrel
in 162 healthy subjects. We then examined the association between these genetic
variants and cardiovascular outcomes in a separate cohort of 1477 subjects with
acute coronary syndromes who were treated with clopidogrel in the Trial to Assess
Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–
Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38


Translation: Does having an inability to activate Plavix lead to ineffect and thus increased risk of event?


the Answer? In short, Yes


In healthy subjects who were treated with clopidogrel, carriers of at least one CYP2C19
reduced-function allele (approximately 30% of the study population) had a relative
reduction of 32.4% in plasma exposure to the active metabolite of clopidogrel, as
compared with noncarriers (P <0.001). p =" 0.01)"> and an increase by
a factor of 3 in the risk of stent thrombosis (2.6% vs. 0.8%; hazard ratio, 3.09; 95% CI, 1.19 to 8.00; P = 0.02).




The Take Away there?

The same......


So why all the fuss??? Well, getting another event because your plavix isn't working is a huge deal.


Even bigger deal? Do you know that every patient who has a heart attack and stented is put on plavix, most people who have angioplasty ALSO are put on Plavix....and with recent literature showing Plavix better than other medications for secondary stroke prevention....This study answers a huge clinical question. "Who will fail Plavix therapy?"


I think we found the answer. Now the second question....


"What the hell do we do about it?"


Three, Maybe 4 solutions


1. The poor metabolism was related to lower drug levels, so BOOST the dose. The problem: Will we have more bleeding events...Plavix is a "blood thinner"

2. We use another medication. With Prasugrel being approved, will this have as big or any effect there? It too requires biotransformation from ProDrug to active metabolite....and had more bleeding

3. We double the dosing schedule, we increase the amount of time Plavix pills are taken, twice a day instead of once a day, hoping to get more converted....

4. We stop PPIs, we do know that PPIs can interfere with 2C19 metabolism, so maybe we should do better med-med-gene reconciliation


The Sherpa Says: We have a clinically actionable test, with action which may not yet be precisely studied. If we know someone is a poor liver or kidney metabolizer what do we do? We avoid that drug. Is that well studied? No.....So what the hell is stopping us from watching these patients more closely and practicing personalized medicine???? One Answer....Physician Ignorance....

Merry Christmas!!! Happy New Year!! Looking forward to my traditional New Years Day post!





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