Tell us about your current approach to testing for platelet reactivity.
St. Francis is a very busy heart institution, one of the busiest sites in the country, and we do several thousand angioplasties a year. Our current approach to platelet function testing has evolved over time. Before an alternative to antiplatelet therapy came out, i.e., prasugrel, we treated people with clopidogrel and aspirin, and had very good success with drug-eluting stents. We have had a low thrombosis and restenosis rate, but questions remained as to what we could do to further lower this rate. Prasugrel came along, and has a different mechanism of action than clopidgrel, but basically, an identical end result. At the cellular level, prasugrel and clopidogrel have identical platelet inhibition. One is just as effective and has the same side effects as the other. One is not any better than the other (if they are both activated).
The difference between the two drugs is very simple: prasugrel needs one enzyme, as a prodrug, to be activated, and clopidogrel needs two. The second enzyme required by clopiodogrel makes all the difference in terms of platelet inhibition. Genetically, some people have no effectiveness with the second enzyme, and other people have mild to moderate effectiveness. The second enzyme also competes with other drugs, such as proton pump inhibitors, for use. Studies have shown anywhere from 30-50% of people taking clopidogrel may not have platelet inhibition, as measured by several commercial tests such as VerifyNow (Accumetrics, San Diego, Calif.).
Some people say that although possibly 40% of people taking clopidogrel are not inhibited it’s not clinically relevant, because we don’t see 40% stent thrombosis, so obviously, it’s not important. But they are looking at it incorrectly. If you ask any interventional cardiologist to tell you the standard of care for a patient getting a drug-eluting stent, everybody will tell you dual antiplatelet therapy is required. Yet while most cardiologists state, yes, they want dual antiplatelet therapy, when you put evidence in front of them that 40% of the time you do not have dual antiplatelet therapy with the use of clopidogrel, you hear the argument, we do not see stent thrombosis, so therefore, it is probably not important.
At St. Francis Hospital, we did a study looking specifically at antiplatelet therapy at the time of drug-eluting stents in patients who either were on antiplatelet drugs such as clopidogrel or prasugrel, or who were on nothing and were loaded. We loaded every patient, and measured antiplatelet activity in every patient. When we measured everyone, we found that just about 100% of people who were loaded with prasugrel inhibited with a platelet reactivity unit (PRU) of less than 230 (a PRU lower than 230 indicates a good response, while a higher number indicates less than optimal response.) Forty-five percent (45%) of those with clopidogrel did not inhibit in our study. Now, that in itself is nothing new. Here is what we did differently. We then reloaded people who did not inhibit with the other drug, and re-measured. In the 45% group of clopidogrel that did not inhibit, when they were reloaded with prasugrel, they all inhibited, and there were no increased major adverse cardiac events (MACE) in terms of bleeding in the first 30 days. In other words, it was safe to give a second reload. Essentially, the 45% of people not inhibited with clopidogrel were taking a placebo, so of course there would not be increased bleeding.
The reason TRITON-TIMI 381 and other studies showed that prasugrel was more effective in terms of MACE in unstable angina and myocardial infarction patients is because a good percentage of the patients on clopidogrel were not inhibited. These patients were essentially taking single antiplatelet therapy (i.e., aspirin). In these studies, if you take out the patients who were nonresponders to clopidogrel, the remaining clopidogrel-responsive patients will have the same good effect of not having stent thrombosis, but also the same increased bleeding of the prasugrel group. If you had 1,000 people on clopidogrel and 1,000 people on prasugrel, and for argument’s sake, 600 people on clopidogrel were inhibited and 400 were not, and 1,000 people were inhibited with prasugrel, well, who is going to have more bleeding? Forty percent (40%) of the people taking clopidogrel are taking placebo — of course they are not going to have as much bleeding! This is why all the negative bleeding press came out on prasugrel. When physicians today say, I don’t give prasugrel because I am afraid of bleeding, well, that is simply not understanding the mechanism of action of these drugs. If you believe that dual antiplatelet therapy is the mainstay of therapy for drug-eluting stents, then you can’t argue the fact that currently we now have a commercially available way to measure whether or not that antiplatelet therapy is effective (in our study, we did it with VerifyNow). We have an obligation to check inhibition and treat accordingly.
So what do we do in our lab? First, everybody is checked for platelet inhibition. Not just in our study, but I now check everyone. The problem with prasugrel is that the FDA, because of the bleeding of some high-risk subgroups in the trials, issued a black box warning saying if patients are over 75 or if have had a transient ischemic attack (TIA), be careful about giving prasugrel. This handcuffs you. For instance, if we have a patient who is 76 and received a drug-eluting stent, the FDA recommends giving this patient clopidogrel, not prasugrel. But if I measure the patient’s PRU and they are not inhibited, what I do then? If I give prasugrel, and the patient bleeds, I will have a malpractice lawyer sue me, because the FDA issued a black box warning. If I don’t give it, and the patient restenoses, the argument would be that you measured PRU and he was uninhibited. I could have that same malpractice lawyer suing me. The FDA has created a situation where it is very difficult to appropriately treat your patients. What I do is document my thinking and treat my patient with the best therapy available. I do treat people with prasugrel who are over 75 when clopidgrel does not inhibit them. In OASIS2, they doubled the dose of clopidogrel to 150 mg for 30 days and had the same low stent thrombosis rates as prasugrel. A higher PRU means less stent thrombosis. The problem is, most people don’t measure platelet inhibition. One of the biggest issues today with antiplatelet drugs in drug-eluting stent patients is the question of how long you treat a patient with clopidogrel or prasugrel. The surgeons especially want to know. It used to be 3 months, 6 months, 1 year, 2 years, and now a thousand years. Everyone wonders, at three months should we stop clopidogrel — but they don’t even measure P2Y12 platelet assay. If the patient is uninhibited, there is no problem stopping it, because it is not working. At St. Francis, we measure everyone’s platelet inhibition, and if you are not inhibited, we give you the alternative drug, and re-measure you to make sure you are inhibited. When I have patients who are going for surgical procedures, I measure to see if they are inhibited to guide me on when I can stop the drug.
I think that there are people who are aspirin insensitive as well. Perhaps the reason non-responders on clopidogrel don’t have stent thrombosis in the 40% range is because we only need single antiplatelet therapy. Maybe the people that do stent thrombose are the patients who are both aspirin insensitive and clopidogrel insensitive, and that might come out to 4%.
Can you tell us more about the study you did at St. Francis?
We had two arms. One arm was what I would call the “virgin” arm, where someone was coming in for a stent, never had stenting performed, and wasn’t on any antiplatelet therapy. This arm gave the results I quoted above. The second arm was people on chronic antiplatelet therapy, whether it was clopidogrel or prasugrel. The numbers for prasugrel inhibition were still pretty close to 100%, and the numbers for clopidogrel were around 50%.
Today, we assume we want dual antiplatelet therapy, but the reality is more complex. For 50% of people taking clopidogrel, it is not working. There has to be something else causing stent thrombosis. I think 5 years in the future, we probably won’t be giving dual antiplatelet therapy. We will probably ultrasound everybody, get a great result, measure platelet reactivity with a single drug, and if it’s working, you might be done.
You mentioned testing patients going in for surgery. Do test results change over time?
No one knows the answer to that. In order to do what you just said, more investigation would be required do a much more extensive test to assess what is going on. If you are taking clopidogrel, and I measured your platelet inhibition and you aren’t inhibited, it could be because you were taking Nexium. If you stop taking Nexium, you might be inhibited because this second enzyme wouldn’t be competing for both drugs. But the point is that if a patient needs surgery and isn’t inhibited, what’s the harm of stopping the clopidogrel?
If it is a patient who is a year out with a stent to an obtuse marginal branch, am I going to continue them on dual therapy longer than a year if he is not inhibited? Probably not. But if it was a proximal left anterior descending coronary artery lesion and it was 5 months out, yes, I’d probably put him back on something. Either I would re-measure him at a higher dose of clopidogrel at 150 or put him on prasugrel. So I could do genetic testing to see whether it is an enzyme problem, drug competition, hyper metabolic state or inflammatory state, but the point is that at the time of surgery, if the patient is not inhibited, I don’t have a problem telling the surgeon to stop the clopidogrel for the surgery.
Why not just switch everybody over to prasugrel (minus the FDA restrictions)?
I do. I use prasugrel for every patient unless they fall under the black box warning (I think the warning should be revisited). Both drugs, clopidogrel and prasugrel, are equally effective when activated. But if half of the patients receiving clopidogrel are not activated, it is not effective. If you give an elderly person a blood thinner, they are going to have an increased risk of bleeding. That’s a side effect of both clopidogrel and prasugrel, if the drugs are working. The reason why prasugrel got the black box warning against TIA or stroke is that these patients bled more, but they were competing against a non-antiplatelet drug that was working half the time.
Who do I give clopidogrel to? People who have contraindications like a stroke or TIA. When I measure these people, if they are not inhibited, I double the post dose to 150 mg and measure it again. If they are still not inhibited, I speak to the patient or referring doctor, and say, you have two choices here. You can take 150 mg, not be inhibited, and run the risk of stent thrombosis, or you can look at the FDA warning and understand I am giving you an alternative to switch to prasugrel, which is a contraindication, but in your situation and as your physician, I personally think it is the right thing to do. I educate them with all the data.
What about timing of measurement? Post PCI, isn’t platelet reactivity affected by what you are doing in the vessel?
We did what was recommended by the company. We measured the platelet inhibition later with clopidogrel than with prasugrel. It was 4-6 hours post procedure for clopidogrel and 2-4 hours for prasugrel.
There are several companies that do platelet inhibition. There are two that are commercially available. We chose to go with VerifyNow, for several reasons. It is easy to do. It is not cost-prohibitive and is basically accepted around the world as an effective antiplatelet drug test or measurement.
Were there any practical challenges to implementing the testing?
Not really. We have 6 very busy labs, with turnover every 30-60 minutes. We tell the research nurse either in the beginning or the end of the study to draw a sample. If it is a patient for the virgin arm, who has never been on antiplatelet therapy before, we do it in the lab, but if we are testing after the patient is loaded, then they do it on the unit. When we first started doing the study, it was not so clear-cut that we were going to expand our platelet function testing. But the results were so dramatic that in the last 6 months, I would say that we have been testing everybody.
Dr. Shlofmitz can be contacted at firstname.lastname@example.org.
- Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007 Nov 15;357(20):2001–2015.
- Mehta SR, Tanguay JF, Eikelboom JW, et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 2010 Oct 9;376(9748):1233–1243.