Testing for Clopidogrel Non-Responsiveness in the PCI Patient

What does “platelet resistance” mean? A better term to use would be clopidogrel non-responsiveness, or, even more specifically, high platelet reactivity while on clopidogrel (Plavix) therapy. Clopidogrel exerts its anti-platelet effect by blocking the platelet P2Y12 receptor. In the body, ADP binds this receptor (i.e., is an agonist), resulting in platelet activation and aggregation. “On-treatment reactivity” refers to the strength of the platelets’ response when exposed to ADP while on clopidogrel therapy. Classically, we can measure this ex vivo, or outside the body, by doing a test called light transmittance aggregometry (LTA) — we put a sample of a patient’s blood in a test tube and adjust it for the concentration of platelets. We can then compare how well light is transmitted through the tube before and after ADP is added. The more reactive the platelets after exposure to ADP, the more platelets will clump and more light will be transmitted through the tube. If clopidogrel is exerting a strong anti-platelet effect, platelets won’t clump together after ADP exposure, and little light will be transmitted; if clopidogrel is not doing anything, then the platelets will clump together quite a bit and the light transmission will be similar to a reference sample that has been depleted of platelets. We can broadly categorize the effect of clopidogrel in 2 ways. The first is to look at the change in platelet reactivity before and after clopidogrel exposure — providing us a “percent” response. For example, if a patient has a 30% response, then clopidogrel caused a 30% reduction in platelet reactivity from baseline, prior to clopidogrel therapy. Figuring this out requires a blood sample prior to giving a patient clopidogrel, which can be a real challenge in clinical practice. Alternatively — and more simply — one can just measure the platelet reactivity after a patient is already on clopidogrel, which is probably more clinically relevant, since events are likely caused by how sticky one’s platelets are on clopidogrel, rather than how much of a change in stickiness has been caused by clopidogrel. We can further categorize patients with very sticky platelets despite clopidogrel as having “high platelet reactivity” — these may be the patients who are at highest risk of ischemic events. Platelet reactivity on clopidogrel therapy can be measured in other ways than light transmittance aggregometry. However, all of these tests rely on a similar concept — measuring what happens to the platelet after exposure to ADP. What type of patients are more likely to have platelet resistance? That’s a great question. The underlying question here is, what is the mechanism of high platelet reactivity on clopidogrel, and how can I identify patients who are at risk? Clopidogrel needs to be converted to its active metabolite to exert an effect on the P2Y12 receptor, and it appears that the variability in platelet responsiveness is predominantly due to variation in the generation of the active metabolite. Other, less likely, actors may include genetic differences in the P2Y12 receptor itself. The generation of the active metabolite is mediated primarily by enzymes in the liver. There are certain genetic polymorphisms, or variability in people’s genes, that affect the activity of the enzymes that metabolize clopidogrel. In particular, there is an enzyme called CYP2C19, and patients who have reduced function CYP2C19 enzymes have less efficient generation of the clopidogrel active metabolite, higher platelet reactivity and more frequent cardiovascular events, despite clopidogrel therapy. However, despite this observed link between genetic variability and high platelet reactivity on clopidogrel, things are more complicated than they might appear. There are many patients who have normal enzymes with good function, yet have high platelet reactivity. There are some patients who have weak enzymes with reduced function, yet have normal or low platelet reactivity. Therefore, it is a more complicated picture, unfortunately, than just our genes. We need more data with larger sample sizes to look at the whole mix of genotype, clinical characteristics and demographics to determine what are the true predictors of high on-treatment platelet reactivity. We know already that in addition to genotype, things like diabetes mellitus are important. There are likely baseline clinical characteristics that also result in high platelet reactivity, possibly because of high baseline reactivity before patients even get clopidogrel. Can you tell us about the GRAVITAS (Gauging Responsiveness With A VerifyNow Assay-Impact On Throm-bosis And Safety) trial? Prospective observational studies have shown that there is an association between high platelet reactivity on clopidogrel and ischemic events after percutaneous coronary intervention (PCI). The unanswered question is, what can we do about it? GRAVITAS is testing whether individualizing the dose of clopidogrel after PCI based on a patient’s platelet function safely reduces ischemic events over follow up. We are using a point-of-care platelet function test called the Accumetrics VerifyNow P2Y12 Assay. This is a variation of light-transmitted aggregometry that uses whole blood, and can be done at the point-of-care or in a clinical laboratory. Therefore, it is simple to use and provides results quickly. In several observational, single-center studies, the result of this point-of-care function assay have been associated with outcomes after PCI. There does seem to be a good correlation between the results of the VerifyNow Assay and light-transmitted aggregometry, which is done in a more basic science research type of setting. In GRAVITAS, patients who get a drug-eluting stent during PCI are treated with clopidogrel as per standard of care, and then have their platelet function tested the morning after PCI. Patients who have high platelet reactivity according to the platelet function test are then randomized to either another clopidogrel loading dose and then high-dose maintenance clopidogrel, 150mg/ day, or a placebo loading dose followed by standard clopidogrel, 75mg/day. The patients are then followed for 6 months. We’ll also be following a random sample of patients who don’t have high platelet reactivity and we’ll be following them on standard clopidogrel therapy as well. From this large, randomized study, we’ll be able to see, first, whether increasing the clopidogrel dose in patients with high on-treatment platelet reactivity reduces ischemic events after PCI. Secondarily, we will also be able to confirm that high platelet reactivity is associated with increased events compared to normal platelet reactivity. Is there anything that can interfere with the test results? That’s an important point. There are several medications that can interfere with the assay’s results. Most importantly, glycoprotein IIb/IIIa inhibitors can confound the results so they are not interpretable. There are potentially other medications which can affect platelet reactivity and which may affect the results of the platelet function test. For example, aspirin may have some small effects on ADP-induced reactivity. This is probably not clinically important, however, since what one wants to see is the overall effect of antiplatelet medication on platelet reactivity. I think we are beginning to get a handle on the appropriate thresholds or diagnostic cut-offs for high on-treatment reactivity, but these data need to be confirmed in a randomized fashion and in bigger studies. We also need to show in a randomized, prospective fashion that changing our patient management based on this test is clinically useful and safe. Dr. Price can be contacted at price.matthew@scrippshealth.org.

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