Platelet response in practice: Applying new insights and tools for testing and treatment

WHAT ROLE FOR THIENOPYRIDINE PRETREATMENT?

Dr. Bhatt: Dr. Sabatine, you presented data from the large TRITON-TIMI 38 trial comparing prasugrel with clopidogrel. I’m interested in how you would use prasugrel in practice, assuming it receives marketing approval, especially in light of its bleeding risk, particularly in patients in whom coronary artery bypass graft surgery (CABG) is planned. Many hospitals pretreat patients with clopidogrel in the emergency department. How would you manage a patient who shows up in the emergency room with ACS? Would you give clopidogrel, would you wait and give prasugrel, or would you do something else? If you gave clopidogrel, what loading dose would you use—300 mg, 600 mg, or, as some have suggested, 900 or 1,200 mg?

Dr. Sabatine: I am a strong proponent of pretreatment. Data from multiple studies show a benefit to this strategy, and even the original CURE trial showed a roughly 30% reduction in ischemic events within the first 24 hours of clopidogrel initiation.⁷

I think the dosing strategy depends on how the patient is going to be managed. If management is going to be conservative, then I would start the patient on 300 mg of clopidogrel when he or she came in. If the patient is going to the cardiac catheterization laboratory in a few hours, I would pretreat with 600 mg of clopidogrel. For prasugrel, the need for pretreatment is less clear, given the drug’s faster onset of action and greater degree of platelet inhibition. In the TRITON-TIMI 38 study,¹⁰ prasugrel was given, by and large, after diagnostic angiography, and thus one could use that approach in practice.

In terms of clopidogrel versus prasugrel, I would embrace prasugrel for the large majority of my patients, being mindful of the risk of bleeding. I would not hesitate to give the medication to diabetics or to younger, more robust patients. The 50% reduction in stent thrombosis with prasugrel versus clopidogrel in TRITON-TIMI 38 is huge,¹¹ given that the risk of death with stent thrombosis is probably 25% or greater. So I would want to have prasugrel on board to reduce the risk of stent thrombosis, especially if a drug-eluting stent were being implanted.

Dr. Bhatt: Dr. Alexander, let’s get your take on a similar scenario. Assuming that prasugrel gains marketing approval, how would you manage patients with non-ST-elevation MI who present to the emergency department? Would you pretreat with clopidogrel? Would you wait until angiography and then, depending on the anatomy, treat with prasugrel? Or would you potentially pretreat with prasugrel, which has not been studied and would not be a labeled indication? How would you reconcile the data?

Dr. Alexander: At Duke, I expect that prasugrel will not be used prior to the catheterization laboratory in patients with non-ST-elevation ACS due to concerns about whether the patients will undergo PCI or be managed medically or with CABG.

Dr. Bhatt: That makes sense, since there was a fair amount of bleeding with prasugrel in those patients in TRITON-TIMI 38.

Dr. Alexander: Correct. Moreover, at Duke we don’t use as much upstream clopidogrel as we would, based on the evidence, if I were managing all the patients. There is still a lot of pushback about upstream clopidogrel from our surgeons because patients are going to surgery quickly these days, sometimes just a day after catheterization, and that’s when a loading dose of clopidogrel can be problematic. We are also still fairly heavy users of glycoprotein IIb/IIIa inhibitors.

Where I can see prasugrel being used prior to the cath lab at Duke is in ST-elevation MI, where the rate of PCI is very high. In primary angioplasty for ST-elevation MI, it would likely be given upstream. The bigger issue for us will be that we serve as a referral base for a lot of regional hospitals, and thus have some influence on their practices.

Dr. Bhatt: In that case, what would you advise those regional hospitals to do for non-ST-elevation MI?

Dr. Alexander: For the time being, we would advise continuing with our current practice, which is to load clopidogrel in patients in whom there is a reasonable certainty that CABG will not be performed, and to use glycoprotein IIb/IIIa inhibitors in high-risk patients. As we get more experience with prasugrel or with additional trial results, however, that practice could easily change.

Dr. Bhatt: So you would still use glycoprotein IIb/IIIa inhibitors?

Dr. Alexander: Yes, I advocate upstream clopidogrel use, but not all my colleagues do. Based on the guidelines, I’d use one or the other—either clopidogrel or a glycoprotein IIb/IIIa inhibitor. As I mentioned in my talk, if a patient is at high risk for bleeding, I am more inclined to use clopidogrel, although patients at higher risk of bleeding are often at higher risk for ischemic events as well.

WHAT’S DRIVEN THE DROPOFF IN GLYCOPROTEIN IIb/IIIa INHIBITOR USE?

Dr. Bhatt: While we’re on the topic of glycoprotein IIb/IIIa inhibitors, a question card from the audience asks why there has been a decrease in glycoprotein IIb/ IIIa inhibitor use and whether this decline is appropriate or inappropriate. Have clopidogrel pretreatment, higher loading doses of clopidogrel, and use of the direct thrombin inhibitor bivalirudin contributed to the decrease in glycoprotein IIb/IIIa inhibitor use?

Dr. Alexander: I do think that the decline has been driven by the changing environment, with greater use of other antithrombotic strategies that include clopidogrel and bivalirudin, as you suggest, as well as an increased attention to bleeding. From an evidence-based standpoint, we don’t know whether the decrease in glycoprotein IIb/IIIa use is appropriate or not because the studies of these agents were conducted before the widespread upstream use of clopidogrel and bivalirudin. Clopidogrel is attractive because it’s a pill given as one dose in the emergency department, the wards, or the catheterization laboratory, rather than a much more complicated infusion with weight-based dosing and dosage adjustments based on creatinine clearance. It is possible that we should perhaps be dosing clopidogrel the same way, but we don’t know that yet.