DR. FERDINAND: On the other hand, based on the updated guidelines and the 75–100 mg labeling for ticagrelor, that is the recommended maintenance dose, the 81 mg.
DR. FOODY: We have seen a change in paradigm as we have moved to more aggressive dual antiplatelet therapy with loading doses of these other agents. As much as OASIS randomized high (300–325 mg) vs low (75–100 mg) dose aspirin, we appreciate that in general the recommended maintenance dose of aspirin is 81 mg. The current guidelines come down pretty clear as to using 81 mg of aspirin, again, though, with the assumption that everyone is a candidate for dual antiplatelet therapy unless there are major contraindications.
DR. FERDINAND: Very good. You know, I’ve practiced medicine a long time and Dr. Lavie, I know you have, too. I can remember when we didn’t do a lot of loading with clopidogrel when it was first released, but looking at the adjunctive antithrombotic therapy in the new STEMI guidelines, they specifically give doses. Clopidogrel, they say 600 mg as early as possible or at the time of PCI; prasugrel, 60 mg, same thing, as early as possible or at the time; ticagrelor, 180 mg.
It appears now that the old idea of whether or not you need to load or not has been answered. Dr. Lavie?
DR. LAVIE: Yes I would agree. Even though the United States Food and Drug Administration (FDA) approved, at least in my understanding, the loading dose of clopidogrel as 300 mg, I think that most clinicians have been routinely using 600 mg load for a decade now. So if you are going to be using clopidogrel you should probably use a 600 mg loading dose, generally followed by 75 mg once daily.
I would like to say there are many patients who get treated with clopidogrel. This applies to the PLATO trial as well. Since 46% of patients in the PLATO trial had already received clopidogrel administered in-hospital before getting randomized,2 a clinician can still safely load with ticagrelor 180 mg followed by 90 mg twice daily.
DR. BERGER: I actually think that is an extremely important point because in TRITON they excluded patients who were on baseline clopidogrel. It’s less of a real world trial. There are no data that if somebody’s on clopidogrel that prasugrel beats clopidogrel. The trial randomized patients who did not receive clopidogrel early on in the emergency department. I think that’s an important distinction between the trials.
DR. FERDINAND: Let me just make a note for the purposes of our roundtable. The FDA labeling for clopidogrel specifically still mentions 300 mg. The alternative of 600 mg is in the guidelines, as early as possible or at the time of PCI with a Class I evidence B recommendation.
DR. FOODY: Keith, one more thing. Just to be clear, we talked about the medically managed patients in NSTEMI, but similarly in STEMI, in medically managed STEMI only ticagrelor and clopidogrel have been studied, but prasugrel was not looked at.
DR. LAVIE: Yes, and Dr. Foody said this in the NSTEMI discussion as well. Prasugrel only has data and is only approved in combination with PCI, since the TRITON study was all PCI patients. Then the following study was the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY-ACS) trial, and it did not show any benefit of prasugrel vs clopidogrel in medically managed patients. Therefore, I would totally agree that the only utilization for prasugrel should be in patients who are managed with PCI, with the only advantage compared with ticagrelor is once daily chronic dosing compared with twice daily with ticagrelor, whereas unlike prasugrel, ticagrelor is not contra indicated in patients with prior transient ischemic attack (TIA) or stroke and only ticagrelor has data for superiority over clopidogrel for cardiovascular and all-cause mortality (the official FDA indication includes the superior wording for cardiovascular death but not for all-cause mortality).
DR. BERGER: One minor thing. We were talking about the aspirin doses earlier and maybe I missed this, but clearly, in ACS the loading dose of aspirin can still be 325 mg. Even if one is using ticagrelor, the maintenance dose needs to be less than 100 mg per day and typically the 81 mg per day in the United States. The loading dose either in the urgent care clinic, in the medical office, or the emergency room is still 162 mg to 325 mg of aspirin.
DR. FERDINAND: You’re absolutely correct. In the guidelines they give 162 mg to 325 mg, but clearly our whole discussion on the 81 mg as a preferred maintenance dose was specifically with ticagrelor but with other agents if desired. That was only a Class IIa. It’s a Class Ib for 162 mg to 325 mg loading dose for all.
Let’s go to maintenance doses and duration of therapy. Clopidogrel has been around a long time. It’s generic and readily available. It’s at 75 mg. We have prasugrel, 10 mg or 5 mg and ticagrelor, 90 mg (twice a day). The first question is, does duration of therapy make a difference, i.e. 12 months either for a drug-eluting stent or bare metal stent? Is there a difference for timing?
DR. LAVIE: I would say no.
DR. BERGER: Right, I agree. I think following an ACS we have shown that dual antiplatelet therapy is effective at decreasing cardiovascular events for 12 months. That has been shown in medically treated ACS as well as following stent implanted ACS. Don’t forget that in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, 20% of the patients underwent a stent implantation of which almost all were bare metal stents.5 It was shown that in that small subgroup there was a very significant benefit in decreasing cardiovascular events. I think we have excellent data showing that whether it is a bare metal stent or a drug-eluting stent, that two drugs compared to one is significantly better for a year’s duration.
DR. LAVIE: To add to that, Keith, I think that most people would have thought—and we have been practicing it—if a patient could not continue dual antiplatelet therapy for whatever reason, this would be a reason to use a bare metal stent, but a paper that just came out in the last month in JAMA suggested that bare metal stents and drug-eluting stents had about the same risk when dual antiplatelet therapy was discontinued.6
DR. FERDINAND: Dr. Foody, do you agree that the guidelines don’t seem to make a difference for continued dual antiplatelet therapy whether it’s a drug-eluting stent or a bare metal stent? Both had the same level.
DR. FOODY: All things being equal and as long as patients can tolerate dual antiplatelet therapy, we have strong evidence that at least a year provides better benefit. There are also some other nuances. In the setting of primary PCI ticagrelor or prasugrel are now given at presentation. There is also a tendency, although not supported in the guidelines, that when clopidogrel is chosen some may use a 600 mg bolus, followed by 150 mg daily and moving then to 75 mg daily after a week.
DR. FERDINAND: Recognizing that may be preferred, the guidelines are pretty silent on that one week of a higher dose.
DR. FOODY: Exactly.
DR. FERDINAND: Well, let’s talk about personal preference. That may not be initially listed in the guidelines but perhaps in the future would be. Does anyone think we need a higher dose of clopidogrel for that first week?
DR. BERGER: I think that is actually based on OASIS 7 as well. OASIS 7 was a two-by-two comparison trial. We were just talking about the aspirin dose, but they also looked at an initial loading dose of clopidogrel of 600 mg and a week of 75 mg twice a day of clopidogrel vs a 300 mg loading dose and 75 mg a day.3
Now, importantly, and the reason why the guidelines did not adopt it is because it was a negative trial. In the overall population there was no significant benefit. However, among patients who underwent stent implantation there was a significant benefit in decreasing cardiovascular events and a significant decrease in stent thrombosis with the higher dose clopidogrel. I think because of that, many in the interventional field believe that using this higher loading dose and using this double dose clopidogrel is more effective for the first week.
DR. LAVIE: The question is, was it the higher loading dose or was it the higher one-week maintenance dose? I do not think that the trial separated these factors, did it, Dr. Berger?