DR. KLEIMAN: You know, I’ve been impressed that we see less dyspnea than we expect to. I really can count on one hand the number of patients in whom I’ve attributed dyspnea to ticagrelor.
DR. BRENER: I totally agree.
DR. KIRTANE: Oh, really? I was going to say after hearing Neal’s response that Texans might not complain as much as the New Yorkers! I tend to see it more frequently than reported in PEGASUS, which is around 14 percent. Clearly there is some patient and practice variability.
DR. BRENER: I think also that it does help—at least, the way I handle this is to say it may be from that. Give it a month. Usually, it goes away in most people. It’s worth it, because I think there are some benefits in reduction in clinical events, and I think that does it for most people. I agree with … my experience is the same as Neal’s, that I needed to switch very few people because really they just can’t handle this sensation of dyspnea, which I think is very different than the regular heart failure dyspnea. It doesn’t seem to be that much of a deal, I think.
DR. KIRTANE: Let’s just transition quickly to oral anticoagulants (OACs). What do you do in that situation? This is an increasingly prevalent population. What do you think?
DR. BRENER: I’m pretty committed to following the guidelines,10 which is that we should use only clopidogrel with OACs, and I follow pretty much the algorithm, using triple therapy rarely and briefly, if at all, and I use the OAC with clopidogrel alone in most folks. In the young ones who are really at low risk of bleeding, I would use triple therapy, but for most, I go with the guidelines.
DR. KIRTANE: Neal, what do you do?
DR. KLEIMAN: I do the same. They get aspirin for a day or two after they’ve had a PCI, then they come off aspirin. They go home on clopidogrel and an OAC. The problem is that getting that message out is not easy. Some people are really stubborn about it. I’m trying to be polite since we’re on tape, but it gets me angry sometimes.
DR. KIRTANE: No, I know. For me as well, it’s actually, interestingly, one of the few scenarios even in ACS where I will use clopidogrel because of the bleeding risk of either triple therapy or even the stacking of the anticoagulant with the other (and more potent) antiplatelet agents. It’s also, though, a scenario where admittedly without data, we test P2Y12 reactivity. The rationale for that is that if the patient is on clopidogrel and an anticoagulant but he/she is not responding to clopidogrel, then he/she is only on the anticoagulant. If we drop aspirin, these patients would not be on anything other than the anticoagulant, and so in those cases, we’ll use a different agent in conjunction with the anticoagulant despite the fact that with more potent agents, there may be more potential bleeding.
DR. BRENER: That’s a great point, I think.
DR. KIRTANE: One last question to bring up would be bleeding risk in surgery. If you look at the FDA guidance documents on this, typically with prasugrel, you’re supposed to wait seven days,11 with clopidogrel, five days,12 and with ticagrelor, five days.13 Do you find that to be the case, or is there a difference in the pharmacology and half-lives that change how you do that? How do you manage this in real life for a patient who’s going to have upcoming surgery?
DR. KLEIMAN: Depends what kind of surgery you’re talking about. If it’s neurosurgery, they get very anxious about this stuff. If it’s open surgery, less so. I mean abdominal or thoracic.
DR. KIRTANE: Sorin, what do you think?
DR. BRENER: I usually use seven, five, and three. I think with ticagrelor there are good data that three days is sufficient.6 I also think that a lot of it has to do with the perception of the surgeon of what is necessary for hemostasis, and I think that perception is really not based on anything in particular. There’s this magic concept that a certain function of the platelets is necessary, but actually, in in vitro studies and ex vivo studies, it’s absolutely not true, so actually 20 percent platelet function is more than sufficient for hemostasis.
So, I find these numbers arbitrary and mostly a matter of negotiating with the other physician what they feel comfortable with. I feel very comfortable recommending three days off of ticagrelor and five days off of clopidogrel.
Prasugrel, I really don’t use. I haven’t used prasugrel in years. The only people we use it in are those who come in on it, so I don’t switch them, because there’s no indication to switch. There, I think you may need to wait a little longer, but I’m pretty convinced that this is nothing to do with reality. It has to do more with the perception and the comfort of the surgeon that needs to be satisfied. I’m comfortable with those recommendations.
DR. KIRTANE: I agree. First of all, I think that there are a lot of surgeries in which patients don’t even need to discontinue, particularly if they’re on clopidogrel and aspirin, as Neal mentioned. But as far as the days to discontinuation, I think that what the
ONSET/OFFSET study and others really do show is that you can probably come off earlier, with ticagrelor in particular.14 A downside of ticagrelor is that it has bid dosing, but the upside is that because it’s reversible and has a shorter half-life, that may be helpful in that scenario. That may explain some of the bleeding differences that were seen in the trials of ticagrelor compared with other agents. By the way, this may be another scenario where—and I don’t want to be a total advocate of P2Y12 reactivity testing—one can use that testing to determine when patients are not inhibited anymore and therefore expedite the surgery. This approach is one that has been discussed in anesthesia guidelines.15
DR. BRENER: Actually, a paper was just published, a letter in Circulation CV Interventions looking exactly at this issue before CABG, very nice data with point-of-care testing showing that you can optimize the timing by using it.16 I think it’s a great idea.
DR. KLEIMAN: Yes, but remember that more than half the challenge here is selling your case to the surgeon and the anesthesiologist.
DR. BRENER: Right. I know that, yes, but this is a different question altogether, just so that you expedite or make things as smooth as possible. I think that we kind of don’t talk about this, but the reason to want to go to surgery as quickly as it is safe is because there is a certain risk of actual events occurring—we learned that from the PARIS trial.17 Interruptions are relatively benign, but it’s not zero, so there’s no point to wait another three, four, five days before you go to surgery when it’s not necessary. If you can go, you should go get it done and resume, if necessary, the antiplatelet therapies. So, it’s on both ends of the spectrum.
DR. KIRTANE: All right. With that, I think we’ve covered a broad range of topics. Just some brief take-homes.
I think first is that, at least in ACS and PCI, it is important to recognize the importance of platelet inhibition. Also, to recognize that there are differences between P2Y12 inhibitors with respect to potency as well as the onset of these agents. Additionally, when the patient is done with the procedure, if one is using other intravenous agents (particularly cangrelor), there may be issues transitioning between these agents. Typically, I think there was consensus that we try to continue dual antiplatelet therapy for patients particularly at the highest risk, with possible down-titration at a year. Obviously, we will consider down-titration earlier in patients at higher bleeding risk. I think we covered a lot of topics with respect to side effects, discontinuation, and also even concomitant anticoagulant therapy, too. With that, I thank you both, Sorin and Neal, for doing this and look forward to doing this again!