Is Genetic Testing Useful After All?

For some time, the use of genetic testing has been heralded as the answer to many questions and problems that we face in the practice of medicine.  The reality has not gotten much traction, but genetic information may be coming of age.

As readers of my blog know, there is a difference between individuals in their response to the drug clopidogrel (Plavix) which can lead to serious difficulties and even death. As I have blogged in the past, it wasn’t until just recently that we as physicians had any idea that we were not getting what we paid for.   In the past, we as doctors had no choice because we had no drug option except to use it.  As I have blogged, two more drugs are now available and I have also blogged about them extensively.

This blog is about a report from the European Society of Cardiology meeting being held now in Stockholm, Sweden.  There is much heat, but not much fire about genetic testing for clopidogrel resistance and for platelet function testing to decide whether clopidogrel is working or not.  The researchers reporting the data from the large PLATO study comparing clopidogrel to prasugrel, shows that both prasugrel and ticagrelor the third agent which will soon be available, are not affected by the CYP2C19 gene or the ABCB1 gene.  In English this means that there is no variation in drug effect between patients and in effect you “get what you pay for”.

Theoretically, this kind of data would lead people to use these drugs over clopidogrel but the real world is different.  At this time, these drugs are basically the same price, but soon clopidogrel will be generic so we may be under pressure to use it.

One other factoid came to light during this discussion which I have wondered about.  It seems that when clopidogrel doesn’t work, it is almost always in the first 30 days and after that, the effect seems to have no medical significance.  So if you are taking Plavix and are doing well on it, you have no worries.

We as physicians will have to begin to understand these changes.  Just one more thing to remember.

Tags: clopidogrel, genetic testing, Plavix
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What does PLATO give us?

The FDA recently received the submission for a new drug ticagrelor for the treatment of Acute Coronary Syndrome.  As mentioned before, this syndrome is a significant cause of death in the United States.  One in three who suffers from it will have death or another myocardial infarction within a year.  Its effective treatment is vital to our war on cardiovascular death and disability.

Ticagrelor is an oral reversible direct acting inhibitor of the P2Y12 platelet activation site.  This sentence tells you much about the difference between this drug and the other two agents; clopidogrel and prasugrel.  Ticagrelor is reversible and they are not and this drug is a direct action agent and it is not metabolized into the effective agent so it has no biologic variability as clopidogrel does.

Ticagrelor was tested against clopidogrel in 18,624 who had acute coronary syndrome with and without ST segment elevation.  The Plavix group received a 300mg loading dose (the standard at the time the study was done) and then 75mgs a day for one year.  The ticagrelor group received a 180mg loading dose and then 90mg twice a day.

At twelve months the primary endpoint which was death from vascular causes, myocardial infarction or stroke had occurred in 9.8% of the ticagrelor group and 11.7% of the clopidogrel group.  This yielded a statistically significant result P<0.001.  No differences were found in rates of major bleeding 11.6% vs. 11.2% but ticagrelor was associated with a higher rate of major bleeding not related to coronary artery bypass grafting 4.55 vs.3.8%.

This result is different from that of prasugrel, which had better outcomes but at the expense of more bleeding episodes.  This likely stems from the fact that it is better metabolized that Plavix and so “more effective.”  Another “good and bad” feature is that the effect on the platelet is short lived and that is why it must be taken twice a day. 

It remains to be seen if patients will accommodate that.  In general, most patients in my experience like once-a-day drugs.  This drug is twice-a-day and “missing” it may lead to more stent thrombosis in general practice.  Often patients are more “compliant” in studies and don’t live with the real world problems of obtaining their drugs by seeing the doctor or having to deal with Insurance companies that want to change from one drug to another.

This compound does give us the ability to change from Plavix to Brilinta in those patients who will require surgery and allow us to “load” patients in the Emergency room.  Over all this is an advance in the treatment of coronary disease.  I am sure that next will be a member of this class that is once a day.  Slowly but surely we are improving the outcomes of patients with acute coronary syndrome.

Tags: Acute Coronary Syndrome, clopidogrel, Myocardial Infarction, prasugrel, Stroke, Ticagrelor
Posted in Acute Coronary Syndrome, Myocardial Infarction | 1 Comment »

One More Weapon Against the Platelet

As I have discussed, the use of Plavix in patients with coronary artery disease is a complex and somewhat vexing problem.  Plavix has been a useful drug and thankfully works in most patients most of the time.  However, when it doesn’t work, patients are susceptible to stent thrombosis and further myocardial infarctions and even death that could possibly be avoided. 

The problem derives from the lack of our ability to define who has an adequate Plavix platelet effect and who does not.  We have what we call point of care testing but no studies have been conducted to define whether if you use the data and change the dose do you get the effect you want or does it cause harm.

Further, Plavix has one glaring both good and bad property.  Plavix is irreversible so that once you have the drug active; it does not stop and must be “worn off.”  This takes five days in the case of Plavix.  The good news is that if you miss a dose, it doesn’t really matter, but if you need to get rid of the effect you can’t.  You come into the Emergency Room with chest pain and our guidelines say you should be immediately loaded with Plavix.  One hour later, you have a cardiac cath and need coronary artery bypass surgery.  Now you have to wait five days before the surgery or risk receiving many more blood transfusions than you would need on average.

Two new drugs are on the horizon.  One is here and one is coming.  The new drug now available is Effient.  I have blogged about this compound on August 10th and 16th.
Prasugrel (Effient) is another P2Y12 inhibitor that is also irreversible; however, it has a much more predictable effect than clopidogrel, so it is more effective than Plavix in providing a better outcome.  However, the cost is that it causes more bleeding than Plavix especially in petite elderly females, so you have to be careful in patient selection.  It needs to be “worn off” and delays surgery five days unless the surgery can not be postponed.

Coming soon is a third P2Y12 inhibitor, which is a different class of drugs from the first two.  This drug is known as ticagrelor and will be known as Brilinta and was submitted to the FDA on November 19, 2009 for approval.  It should be available by the end of this year.  It was submitted based upon the study PLATO and that will be my next blog.

Tags: Brilinta, clopidogrel, Coronary artery disease, Effient, Plavix, stent thrombosis
Posted in Aortic Aneurysms /Stents / Grafts, Coronary Artery Disease | No Comments »